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  • 1.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brunn: an open source laboratory information system for microplates with a graphical plate layout design process2011Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, nr 1, artikkel-id 179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.

    Results:

    A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.

    Conclusions:

    Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

  • 2.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Carlsson, Lars
    AstraZeneca R&D.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines2014Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 11, s. 3211-3217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.

  • 3.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engkvist, Ola
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carlsson, Lars
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Noeske, Tobias
    Ligand-Based Target Prediction with Signature Fingerprints2014Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 10, s. 2647-2653Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.

  • 4.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lampa, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Large-scale ligand-based predictive modelling using support vector machines2016Inngår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, artikkel-id 39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.

  • 5.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    Resistin Gene Transcription Is Regulated in Adaptive and Innate Immunity in Rheumatoid Arthritis2016Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 904-904Artikkel i tidsskrift (Annet vitenskapelig)
  • 6.
    Andersen, M.
    et al.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Meyer, M. K.
    Aalborg Univ, Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Aalborg Univ, Clin Med, Aalborg, Denmark..
    The Melanocortin System Is Responsive in Disease Driving Immune Cells in Rheumatoid Arthritis and May Offer A Pathway To Curative Treatment2016Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 903-904Artikkel i tidsskrift (Annet vitenskapelig)
  • 7.
    Andersen, M.
    et al.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Meyer, M. K.
    Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark.;North Denmark Reg Hosp, Ctr Clin Sci, Hjorring, Denmark..
    Nagaeva, O.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Andersen, G. N.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF-alfa Inhibition2017Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 1, s. 31-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 8. Andersen, M.
    et al.
    Olesen, M. K.
    Nagaev, I.
    Nagaeva, O.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Andersen, G. N.
    Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis2014Inngår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, s. 25-26Artikkel i tidsskrift (Annet vitenskapelig)
  • 9.
    Eklund, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    An eScience-Bayes strategy for analyzing omics data2010Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11, s. 282-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The omics fields promise to revolutionize our understanding of biology and biomedicine. However, their potential is compromised by the challenge to analyze the huge datasets produced. Analysis of omics data is plagued by the curse of dimensionality, resulting in imprecise estimates of model parameters and performance. Moreover, the integration of omics data with other data sources is difficult to shoehorn into classical statistical models. This has resulted in ad hoc approaches to address specific problems. Results: We present a general approach to omics data analysis that alleviates these problems. By combining eScience and Bayesian methods, we retrieve scientific information and data from multiple sources and coherently incorporate them into large models. These models improve the accuracy of predictions and offer new insights into the underlying mechanisms. This "eScience-Bayes" approach is demonstrated in two proof-of-principle applications, one for breast cancer prognosis prediction from transcriptomic data and one for protein-protein interaction studies based on proteomic data. Conclusions: Bayesian statistics provide the flexibility to tailor statistical models to the complex data structures in omics biology as well as permitting coherent integration of multiple data sources. However, Bayesian methods are in general computationally demanding and require specification of possibly thousands of prior distributions. eScience can help us overcome these difficulties. The eScience-Bayes thus approach permits us to fully leverage on the advantages of Bayesian methods, resulting in models with improved predictive performance that gives more information about the underlying biological system.

  • 10. Fossen, Torgils
    et al.
    Rasoanaivo, Philippe
    Manjovelo, Christian Sambany
    Raharinjato, Fanja Hanitriniala
    Yahorava, Sviatlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yahorau, Aleh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A new protolimonoid from Capuronianthus mahafalensis2012Inngår i: Fitoterapia (Milano), ISSN 0367-326X, E-ISSN 1873-6971, Vol. 83, nr 5, s. 901-906Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    From stem barks of Capuronianthus mahafalensis (Meliaceae) endemic to Madagascar, a new protolimonoid named capulin containing a four membered ring in its side chain was isolated by repeated silica gel column chromatography. Its structure was determined by 1D and 2D NMR spectroscopy and high-resolution MS. To the best of our knowledge, this is the first time that a four-membered ring occurs in the side chain of protolimonoids. 

  • 11. Grigorjeva, Liene
    et al.
    Liepinsh, Edvards
    Razafimahefa, Solofoniaina
    Yahorau, Aleh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yahorava, Sviatlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rasoanaivo, Philippe
    Jirgensons, Aigars
    Wikberg, Jar E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Semisynthesis of Libiguin A and Its Analogues by Trans-Lactonization of Phragmalin2014Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, nr 9, s. 4148-4153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Libiguins are limonoids with highly potent sexual activity enhancing effects, originally isolated from the Madagascarian Meliaceae species Neobeguea mahafalensis, where they exist in only minute quantities. Their low natural abundance has hampered mapping of their biological effects. Here we describe an approach to the semisynthesis of libiguin A and its close analogues 1-3 starting from phragmalin, which is a limonoid present in high amounts in a commercially cultivated Meliaceae species, Chukrasia tabularis, allowing the preparation of libiguins in appreciable quantities.

  • 12. Junaid, M.
    et al.
    Angsuthanasombat, C.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ali, N.
    Katzenmeier, G.
    A straightforward experimental approach to expression, purification, refolding, and enzymatic analysis of recombinant dengue virus NS2B(H)-NS3pro protease2013Inngår i: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 78, nr 8, s. 920-924Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dengue virus threatens around 2.5 billion people worldwide; about 50 million become infected every year, and yet no vaccine or drug is available for prevention and/or treatment. The flaviviral NS2B-NS3pro complex is indispensable for flaviviral replication and is considered to be an important drug target. The aim of this study was to develop a simple and generally applicable experimental strategy to construct, purify, and assay a highly active recombinant NS2B(H)-NS3pro complex that would be useful for high-throughput screening of potential inhibitors. The sequence of NS2B(H)-NS3pro was generated by overlap extension PCR (SOE-PCR) and cloned into the pTrcHisA vector. Hexahistidine-tagged NS2B(H)-NS3pro complex was expressed in E. coli predominantly as insoluble protein and purified to > 95% purity by single-step immobilized metal affinity chromatography. SDS-PAGE followed by immunoblotting of the purified enzyme demonstrated the presence of the NS2B(H)-NS3pro precursor and its autocleavage products, NS3pro and NS2B(H), as 37, 21, and 10 kDa bands, respectively. Kinetic parameters, K (m), k (cat), and k (cat)/K (m) for the fluorophore-linked protease model substrate Ac-nKRR-amc were obtained using inner-filter effect correction. The kinetic parameters K (m), k (cat), and k (cat)/K (m) for Ac-nKRR-amc substrate were 100 mu M, 0.112 s(-1), and 1120 M-1 center dot s(-1), respectively. A simplified procedure for the cloning, overexpression, and purification of the NS2B(H)-NS3pro complex was applied, and a highly active recombinant NS2B(H)-NS3pro complex was obtained that could be useful for the design of high-throughput assays aimed at flaviviral inhibitor discovery.

  • 13. Junaid, M.
    et al.
    Angsuthanasombat, C.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ali, N.
    Katzenmeier, G.
    Modulation of enzymatic activity of dengue virus nonstructural protein NS3 nucleoside triphosphatase/helicase by poly(U)2013Inngår i: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 78, nr 8, s. 925-932Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nonstructural protein 3 (NS3) appears to be the most promising target for anti-flavivirus therapy because of its multiple enzymatic activities that are indispensable for virus replication. NS3 of dengue virus type 2 (DEN2) is composed of two domains, a serine protease in the N-terminal domain (NS3pro) and RNA-stimulated nucleoside triphosphatase (NTPase)/RNA helicase at the C-terminus (NS3h). NS3 plays an important role in viral replication and the coordinated regulation of all the catalytic activities in the full-length NS3 protein. In this study, a plasmid harboring the NS3 helicase domain (NS3h) was constructed by PCR. The 56.5 kDa NS3h protein was purified by metal-chelate affinity chromatography followed by renaturation, mediated by artificial chaperone-assisted refolding, which yielded the active helicase. NTPase activity was assayed with Malachite Green. The NTPase activity in the presence of poly(U) showed a higher turnover number (k (cat)) and a lower K (m) value than without poly(U). The activity increased approximately fourfold in the presence of polynucleotides. This indicates that NTPase activity of dengue NS3 can be stimulated by polynucleotides. A helicase assay based on internal fluorescence quenching was conducted using short internally quenched DNA oligonucleotides as substrates. Significant fluorescence signaling increase was observed in the absence of polynucleotides such as poly(U). No unwinding activity was observed with addition of poly(U). The approach we describe here is useful for the further characterization of substrate specificity and for the design of high-throughput assays aimed at discovery of inhibitors against NS3 NTPase/helicase activities.

  • 14.
    Junaid, Muhammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Chalayut, Chakard
    Laboratory of Molecular and Cellular Microbiology, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhorpathom, Thailand.
    Sehgelmeble Torrejon, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Angsuthanasombat, Chanan
    Laboratory of Molecular and Cellular Microbiology, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhorpathom, Thailand.
    Shutava, Iryna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl ES
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Katzenmeier, Gerd
    Laboratory of Molecular and Cellular Microbiology, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhorpathom, Thailand.
    ­­­­­­­­Enzymatic Analysis of Recombinant Japanese Encephalitis Virus NS2B(H)-NS3pro Protease with Fluorogenic Model Peptide Substrates2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 5, s. e36872-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Japanese encephalitis virus (JEV), a member of the Flaviviridae family, causes around 68,000 encephalitis cases annually, of which 20–30% are fatal, while 30–50% of the recovered cases develop severe neurological sequelae. Specific antivirals for JEV would be of great importance, particularly in those cases where the infection has become persistent. Being indispensable for flaviviral replication, the NS2B-NS3 protease is a promising target for design of anti-flaviviral inhibitors. Contrary to related flaviviral proteases, the JEV NS2B-NS3 protease is structurally and mechanistically much less characterized. Here we aimed at establishing a straightforward procedure for cloning, expression, purification and biochemical characterization of JEV NS2B(H)-NS3pro protease.

    Methodology/Principal Findings

    The full-length sequence of JEV NS2B-NS3 genotype III strain JaOArS 982 was obtained as a synthetic gene. The sequence of NS2B(H)-NS3pro was generated by splicing by overlap extension PCR (SOE-PCR) and cloned into the pTrcHisA vector. Hexahistidine-tagged NS2B(H)-NS3pro, expressed in E. coli as soluble protein, was purified to >95% purity by a single-step immobilized metal affinity chromatography. SDS-PAGE and immunoblotting of the purified enzyme demonstrated NS2B(H)-NS3pro precursor and its autocleavage products, NS3pro and NS2B(H), as 36, 21, and 10 kDa bands, respectively. Kinetic parameters, Km and kcat, for fluorogenic protease model substrates, Boc-GRR-amc, Boc-LRR-amc, Ac-nKRR-amc, Bz-nKRR-amc, Pyr-RTKR-amc and Abz-(R)4SAG-nY-amide, were obtained using inner filter effect correction. The highest catalytic efficiency kcat/Km was found for Pyr-RTKR-amc (kcat/Km: 1962.96±85.0 M−1 s−1) and the lowest for Boc-LRR-amc (kcat/Km: 3.74±0.3 M−1 s−1). JEV NS3pro is inhibited by aprotinin but to a lesser extent than DEN and WNV NS3pro.

    Conclusions/Significance

    A simplified procedure for the cloning, overexpression and purification of the NS2B(H)-NS3pro was established which is generally applicable to other flaviviral proteases. Kinetic parameters obtained for a number of model substrates and inhibitors, are useful for the characterization of substrate specificity and eventually for the design of high-throughput assays aimed at antiviral inhibitor discovery.

  • 15.
    Junaid, Muhammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Proteochemometric Modeling of the Susceptibility of Mutated Variants of the HIV-1 Virus to Reverse Transcriptase Inhibitors2010Inngår i: PLoS ONE, ISSN eISSN-1932-6203, Vol. 5, nr 12, s. e14353-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Reverse transcriptase is a major drug target in highly active antiretroviral therapy (HAART) against HIV, which typically comprises two nucleoside/nucleotide analog reverse transcriptase (RT) inhibitors (NRTIs) in combination with a non-nucleoside RT inhibitor or a protease inhibitor. Unfortunately, HIV is capable of escaping the therapy by mutating into drug-resistant variants. Computational models that correlate HIV drug susceptibilities to the virus genotype and to drug molecular properties might facilitate selection of improved combination treatment regimens.

    Methodology/Principal Findings

    We applied our earlier developed proteochemometric modeling technology to analyze HIV mutant susceptibility to the eight clinically approved NRTIs. The data set used covered 728 virus variants genotyped for 240 sequence residues of the DNA polymerase domain of the RT; 165 of these residues contained mutations; totally the data-set covered susceptibility data for 4,495 inhibitor-RT combinations. Inhibitors and RT sequences were represented numerically by 3D-structural and physicochemical property descriptors, respectively. The two sets of descriptors and their derived cross-terms were correlated to the susceptibility data by partial least-squares projections to latent structures. The model identified more than ten frequently occurring mutations, each conferring more than two-fold loss of susceptibility for one or several NRTIs. The most deleterious mutations were K65R, Q151M, M184V/I, and T215Y/F, each of them decreasing susceptibility to most of the NRTIs. The predictive ability of the model was estimated by cross-validation and by external predictions for new HIV variants; both procedures showed very high correlation between the predicted and actual susceptibility values (Q2 = 0.89 and Q2ext = 0.86). The model is available at www.hivdrc.org as a free web service for the prediction of the susceptibility to any of the clinically used NRTIs for any HIV-1 mutant variant.

    Conclusions/Significance

    Our results give directions how to develop approaches for selection of genome-based optimum combination therapy for patients harboring mutated HIV variants.

  • 16.
    Kindlundh, Anna MS
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bergström, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl ES
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The anabolic-androgenic steroid nandrolone decanoate affects the density of dopamine receptors in the male rat brain2001Inngår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 13, nr 2, s. 291-296Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In recent years a male group of anabolic-androgenic steroid misusers has been identified to share socio-demographic and personality related background factors with misusers of psychotropic substances, as well as being involved in habits of multiple drug use. The present study aimed to assess whether anabolic-androgenic steroids (AAS) would affect the density of the dopamine receptors in areas implicated in reward and behaviour in the male rat brain. The effects of 2 weeks of treatment with i.m. injections of nandrolone decanoate (15 mg/kg/day) on the expression of the D(1)-like and D(2)-like receptors were evaluated by autoradiography. Specific binding of D(1)-like receptors was significantly down regulated in the caudate putamen, the nucleus accumbens core and shell. D(2)-like receptor densities were down regulated in the nucleus accumbens shell, but up regulated in the caudate putamen, the nucleus accumbens core and the ventral tegmental area. These results are compatible with nandrolone induced neuroadaptive alterations in dopamine circuits associated with motor functions and behavioural paradigms known to be affected following AAS misuse.

  • 17.
    Lapins, Maris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Prusis, Peteris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Wikberg, Jarl E S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Proteochemometric modeling of HIV protease susceptibility2008Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 9, s. 181-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND

    A major obstacle in treatment of HIV is the ability of the virus to mutate rapidly into drug-resistant variants. A method for predicting the susceptibility of mutated HIV strains to antiviral agents would provide substantial clinical benefit as well as facilitate the development of new candidate drugs. Therefore, we used proteochemometrics to model the susceptibility of HIV to protease inhibitors in current use, utilizing descriptions of the physico-chemical properties of mutated HIV proteases and 3D structural property descriptions for the protease inhibitors. The descriptions were correlated to the susceptibility data of 828 unique HIV protease variants for seven protease inhibitors in current use; the data set comprised 4792 protease-inhibitor combinations.

    RESULTS

    The model provided excellent predictability (R2 = 0.92, Q2 = 0.87) and identified general and specific features of drug resistance. The model's predictive ability was verified by external prediction in which the susceptibilities to each one of the seven inhibitors were omitted from the data set, one inhibitor at a time, and the data for the six remaining compounds were used to create new models. This analysis showed that the over all predictive ability for the omitted inhibitors was Q2 inhibitors = 0.72.

    CONCLUSION

    Our results show that a proteochemometric approach can provide generalized susceptibility predictions for new inhibitors. Our proteochemometric model can directly analyze inhibitor-protease interactions and facilitate treatment selection based on viral genotype. The model is available for public use, and is located at HIV Drug Research Centre.

  • 18.
    Lapins, Maris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kinome-wide interaction modelling using alignment-based and alignment-independent approaches for kinase description and linear and non-linear data analysis techniques2010Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11, s. 339-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Protein kinases play crucial roles in cell growth, differentiation, and apoptosis. Abnormal function of protein kinases can lead to many serious diseases, such as cancer. Kinase inhibitors have potential for treatment of these diseases. However, current inhibitors interact with a broad variety of kinases and interfere with multiple vital cellular processes, which causes toxic effects. Bioinformatics approaches that can predict inhibitor-kinase interactions from the chemical properties of the inhibitors and the kinase macromolecules might aid in design of more selective therapeutic agents, that show better efficacy and lower toxicity.

    Results

    We applied proteochemometric modelling to correlate the properties of 317 wild-type and mutated kinases and 38 inhibitors (12,046 inhibitor-kinase combinations) to the respective combination's interaction dissociation constant (K-d). We compared six approaches for description of protein kinases and several linear and non-linear correlation methods. The best performing models encoded kinase sequences with amino acid physico-chemical z-scale descriptors and used support vector machines or partial least-squares projections to latent structures for the correlations. Modelling performance was estimated by double cross-validation. The best models showed high predictive ability; the squared correlation coefficient for new kinase-inhibitor pairs ranging P-2 = 0.67-0.73; for new kinases it ranged P-kin(2) = 0.65-0.70. Models could also separate interacting from non-interacting inhibitor-kinase pairs with high sensitivity and specificity; the areas under the ROC curves ranging AUC = 0.92-0.93. We also investigated the relationship between the number of protein kinases in the dataset and the modelling results. Using only 10% of all data still a valid model was obtained with P-2 = 0.47, P-kin(2) = 0.42 and AUC = 0.83.

    Conclusions

    Our results strongly support the applicability of proteochemometrics for kinome-wide interaction modelling. Proteochemometrics might be used to speed-up identification and optimization of protein kinase targeted and multi-targeted inhibitors.

  • 19.
    Lapins, Maris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Proteochemometric Modeling of Drug Resistance over the Mutational Space for Multiple HIV Protease Variants and Multiple Protease Inhibitors2009Inngår i: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 49, nr 5, s. 1202-1210Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The main therapeutic targets in HIV are its protease and reverse transcriptase. A major problem in treatment of HIV is the ability of the virus to develop drug resistance by accumulating mutations in its targets. Acquiring detailed understanding of the molecular mechanisms for the interactions of drugs with mutated variants of the HIV virus is mandatory to be able to design inhibitors that can evade the resistance. Here we have used proteochemometric modeling to simultaneously analyze the interactions of 21 protease inhibitors with 72 unique protease variants. Inhibition data (pK(i)) were correlated to descriptions of chemical and structural properties of the inhibitors and proteases. The proteochemometric model obtained showed excellent fit and predictive ability (R(2)=0.92, Q(2)=0.83, Q(2)(inh)=0.78) and provided quantitative assessments for the contribution of each mutation and their combinations to the decrease in inhibitor activity, both for the whole compounds series as well as for individual compounds. The model revealed the most deleterious mutations in the protease to be D30N, V32I, G48V, I50V, I54V, V82A, I84V, and L90M. The model was further used to identify molecular properties of chemical compounds that are important for their inhibition of multimutated protease variants. Our results give directions how to design novel improved inhibitors.

  • 20.
    Lapins, Maris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Worachartcheewan, Apilak
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Georgiev, Valentin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Prachayasittikul, Virapong
    Nantasenamat, Chanin
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A Unified Proteochemometric Model for Prediction of Inhibition of Cytochrome P450 Isoforms2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e66566-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A unified proteochemometric (PCM) model for the prediction of the ability of drug-like chemicals to inhibit five major drug metabolizing CYP isoforms (i.e. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was created and made publicly available under the Bioclipse Decision Support open source system at www.cyp450model.org. In regards to the proteochemometric modeling we represented the chemical compounds by molecular signature descriptors and the CYP-isoforms by alignment-independent description of composition and transition of amino acid properties of their protein primary sequences. The entire training dataset contained 63 391 interactions and the best PCM model was obtained using signature descriptors of height 1, 2 and 3 and inducing the model with a support vector machine. The model showed excellent predictive ability with internal AUC = 0.923 and an external AUC = 0.940, as evaluated on a large external dataset. The advantage of PCM models is their extensibility making it possible to extend our model for new CYP isoforms and polymorphic CYP forms. A key benefit of PCM is that all proteins are confined in one single model, which makes it generally more stable and predictive as compared with single target models. The inclusion of the model in Bioclipse Decision Support makes it possible to make virtual instantaneous predictions (∼100 ms per prediction) while interactively drawing or modifying chemical structures in the Bioclipse chemical structure editor.

  • 21.
    Lindblom, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Kindlundh, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bergström, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Anabolic androgenic steroid nandrolone decanoate reduces hypothalamic proopiomelanocortin mRNA levels2003Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 986, nr 1-2, s. 139-147Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Supratherapeutical doses of anabolic androgenic steroids (AASs) have dramatic effects on metabolism in humans, and also inhibit feeding and reduce the rate of body weight gain in rats. In order to test the hypothesis that the AAS metabolic syndrome is accompanied by alterations in the central melanocortin system, we evaluated body weight, food intake and hypothalamic agouti-related protein (AgRP) and proopiomelanocortin (POMC) mRNA levels following administration of different doses of the anabolic androgenic steroid nandrolone decanoate. In order to distinguish changes induced by the steroid treatment per se from those resulting from the reduced food intake and growth rate, we also compared the effect of nandrolone decanoate on AgRP and POMC mRNA expression with both normally fed, and food restricted control groups. We here report that administration of nandrolone specifically reduces arcuate nucleus POMC mRNA levels while not affecting the expression level of AgRP. The effect on POMC expression was not observed in the food restricted controls, excluding the possibility that the observed effect was a mere response to the reduced food intake and body weight. These results raise the possibility that some of the metabolic and behavioural consequences of AAS abuse may be the result of alterations in the melanocortin system.

  • 22.
    Nabu, Sunanta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Owasirikul, Wiwat
    Lawung, Ratana
    Isarankura-Na-Ayudhya, Chartchalerm
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Prachayasittikul, Virapong
    Proteochemometric model for predicting the inhibition of penicillin-binding proteins2015Inngår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, nr 2, s. 127-141Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neisseria gonorrhoeae infection threatens to become an untreatable sexually transmitted disease in the near future owing to the increasing emergence of N. gonorrhoeae strains with reduced susceptibility and resistance to the extended-spectrum cephalosporins (ESCs), i.e. ceftriaxone and cefixime, which are the last remaining option for first-line treatment of gonorrhea. Alteration of the penA gene, encoding penicillin-binding protein 2 (PBP2), is the main mechanism conferring penicillin resistance including reduced susceptibility and resistance to ESCs. To predict and investigate putative amino acid mutations causing beta-lactam resistance particularly for ESCs, we applied proteochemometric modeling to generalize N. gonorrhoeae susceptibility data for predicting the interaction of PBP2 with therapeutic beta-lactam antibiotics. This was afforded by correlating publicly available data on antimicrobial susceptibility of wild-type and mutant N. gonorrhoeae strains for penicillin-G, cefixime and ceftriaxone with 50 PBP2 protein sequence data using partial least-squares projections to latent structures. The generated model revealed excellent predictability (R (2) = 0.91, Q (2) = 0.77, Q (Ext) (2) = 0.78). Moreover, our model identified amino acid mutations in PBP2 with the highest impact on antimicrobial susceptibility and provided information on physicochemical properties of amino acid mutations affecting antimicrobial susceptibility. Our model thus provided insight into the physicochemical basis for resistance development in PBP2 suggesting its use for predicting and monitoring novel PBP2 mutations that may emerge in the future.

  • 23. Nantasenamat, Chanin
    et al.
    Simeon, Saw
    Owasirikul, Wiwat
    Songtawee, Napat
    Lapins, Maris
    Prachayasittikul, Virapong
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Illuminating the Origins of Spectral Properties of Green Fluorescent Proteins via Proteochemometric and Molecular Modeling2014Inngår i: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 35, nr 27, s. 1951-1966Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Green fluorescent protein (GFP) has immense utility in biomedical imaging owing to its autofluorescent nature. In efforts to broaden the spectral diversity of GFP, there have been several reports of engineered mutants via rational design and random mutagenesis. Understanding the origins of spectral properties of GFP could be achieved by means of investigating its structure-activity relationship. The first quantitative structure-property relationship study for modeling the spectral properties, particularly the excitation and emission maximas, of GFP was previously proposed by us some years ago in which quantum chemical descriptors were used for model development. However, such simplified model does not consider possible effects that neighboring amino acids have on the conjugated pi-system of GFP chromophore. This study describes the development of a unified proteochemometric model in which the GFP chromophore and amino acids in its vicinity are both considered in the same model. The predictive performance of the model was verified by internal and external validation as well as gamma-scrambling. Our strategy provides a general solution for elucidating the contribution that specific ligand and protein descriptors have on the investigated spectral property, which may be useful in engineering novel GFP variants with desired characteristics.

  • 24. Neumann Andersen, G.
    et al.
    Andersen, M.
    Nagaeva, O.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Dermal Melanocortin Receptor Rebound in Diffuse Systemic Sclerosis after Anti-TGFβ1 Antibody Therapy2012Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 76, nr 5, s. 478-482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Disturbed transforming growth factor beta (TGFβ) signalling leads to enhanced synthesis of extracellular matrix (ECM), which is manifested as systemic sclerosis (SSc), but this may be attenuated by the melanocortin system. Here, we report of rebound reaction in the gene expression of melanocortin receptor (MCR) subtypes and of the precursor of these receptors' ligands, the pro-opio-melanocortin protein (POMC), in the acute skin lesion of diffuse systemic sclerosis (dSSc) after treatment with a recombinant human anti-TGFβ1 antibody. Biopsies, taken from the leading edge of the skin lesion, before and after treatment of a patient with recent onset dSSc, were examined. Before treatment, increased levels of TGFβ mRNA and suppressed levels of POMC mRNA and MCR subtypes MC 1-3, 5R mRNAs were seen in the lesion, compared with healthy controls. After treatment, there was a rebound expression of POMC, MC 2, 3, 5R mRNAs. As the melanocortin system regulates collagen and melanin production, our findings add a new understanding to the pathogenetic mechanisms involved in the acute skin lesion of dSSc, which is characterized by enhanced ECM formation and changes in skin pigmentation.

  • 25.
    Prachayasittikul, Veda
    et al.
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Prathipati, Philip
    Natl Inst Biomed Innovat, Osaka, Japan.;Natl Inst Hlth & Nutr, Osaka, Japan..
    Pratiwi, Reny
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Phanus-umporn, Chuleeporn
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Malik, Aijaz Ahmad
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Schaduangrat, Nalini
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Seenprachawong, Kanokwan
    Mahidol Univ, Fac Med Technol, Dept Clin Microscopy, Bangkok, Thailand..
    Wongchitrat, Prapimpun
    Mahidol Univ, Fac Med Technol, Ctr Res & Innovat, Bangkok, Thailand..
    Supokawej, Aungkura
    Mahidol Univ, Fac Med Technol, Dept Clin Microscopy, Bangkok, Thailand..
    Prachayasittikul, Virapong
    Mahidol Univ, Fac Med Technol, Dept Clin Microbiol & Appl Technol, Bangkok, Thailand..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
    Exploring the epigenetic drug discovery landscape2017Inngår i: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 12, nr 4, s. 345-362Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Introduction: Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics. Expert opinion: Despite significant interests in targeting epigenetic modifiers as a therapeutic route, certain classes of target proteins are heavily studied while some are less characterized. Thus, such orphan target proteins are not yet druggable with limited report of active modulators. Current research points towards a great future with novel drugs directed to the many complex multifactorial diseases of humans, which are still often poorly understood and difficult to treat.

  • 26.
    Pratiwi, Reny
    et al.
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand.;Setia Budi Univ, Dept Med Lab Technol, Fac Hlth Sci, Surakarta 57127, Indonesia..
    Malik, Aijaz Ahmad
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Schaduangrat, Nalini
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Prachayasittikul, Virapong
    Mahidol Univ, Fac Med Technol, Dept Clin Microbiol & Appl Technol, Bangkok 10700, Thailand..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Shoombuatong, Watshara
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    CryoProtect: A Web Server for Classifying Antifreeze Proteins from Nonantifreeze Proteins2017Inngår i: Journal of Chemistry, ISSN 2090-9063, E-ISSN 2090-9071, artikkel-id 9861752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Antifreeze protein (AFP) is an ice-binding protein that protects organisms from freezing in extremely cold environments. AFPs are found across a diverse range of species and, therefore, significantly differ in their structures. As there are no consensus sequences available for determining the ice-binding domain of AFPs, thus the prediction and characterization of AFPs from their sequence is a challenging task. This study addresses this issue by predicting AFPs directly from sequence on a large set of 478 AFPs and 9,139 non-AFPs using machine learning (e.g., random forest) as a function of interpretable features (e.g., amino acid composition, dipeptide composition, and physicochemical properties). Furthermore, AFPs were characterized using propensity scores and important physicochemical properties via statistical and principal component analysis. The predictive model afforded high performance with an accuracy of 88.28% and results revealed that AFPs are likely to be composed of hydrophobic amino acids as well as amino acids with hydroxyl and sulfhydryl side chains. The predictive model is provided as a free publicly available web server called CryoProtect for classifying query protein sequence as being either AFP or non-AFP. The data set and source code are for reproducing the results which are provided on GitHub.

  • 27.
    Prusis, Peteris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Junaid, Muhammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Petrovska, Ramona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yahorava, Sviatlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yahorau, Aleh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Katzenmeier, Gerd
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases2013Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 434, nr 4, s. 767-772Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A series of 45 peptide inhibitors was designed, synthesized, and evaluated against the NS2B-NS3 proteases of the four subtypes of dengue virus, DEN-1-4. The design was based on proteochemometric models for Michaelis (K-m) and cleavage rate constants (k(cat)) of protease substrates. This led first to octapeptides showing submicromolar or low micromolar inhibitory activities on the four proteases. Stepwise removal of cationic substrate non-prime side residues and variations in the prime side sequence resulted finally in an uncharged tetrapeptide, WYCW-NH2, with inhibitory K-i values of 4.2, 4.8, 24.4, and 11.2 mu M for the DEN-1-4 proteases, respectively. Analysis of the inhibition data by proteochemometric modeling suggested the possibility for different binding poses of the shortened peptides compared to the octapeptides, which was supported by results of docking of WYCW-NH2 into the X-ray structure of DEN-3 protease.

  • 28.
    Prusis, Peteris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Yahorava, Sviatlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Petrovska, Ramona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Niyomrattanakit, Pornwaratt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Katzenmeier, Gerd
    Wikberg, Jarl E S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases2008Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, nr 20, s. 9369-9377Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The prime side specificity of dengue protease substrates was investigated by use of proteochemometrics, a technology for drug target interaction analysis. A set of 48 internally quenched peptides were designed using statistical molecular design (SMD) and assayed with proteases of four subtypes of dengue virus (DEN-1-4) for Michaelis (K(m)) and cleavage rate constants (k(cat)). The data were subjected to proteochemometrics modeling, concomitantly modeling all peptides on all the four dengue proteases, which yielded highly predictive models for both activities. Detailed analysis of the models then showed that considerably differing physico-chemical properties of amino acids contribute independently to the K(m) and k(cat) activities. For k(cat), only P1' and P2' prime side residues were important, while for K(m) all four prime side residues, P1'-P4', were important. The models could be used to identify amino acids for each P' substrate position that are favorable for, respectively, high substrate affinity and cleavage rate.

  • 29.
    Raine, Amanda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Lovmar, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ehrenberg, Måns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Trigger factor binding to ribosomes with nascent peptide chains of varying lengths and sequences2006Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, nr 38, s. 28033-28038Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Trigger factor (TF) is the first protein-folding chaperone to interact with a nascent peptide chain as it emerges from the ribosome. Here, we have used a spin down assay to estimate the affinities for the binding of TF to ribosome nascent chain complexes (RNCs) with peptides of varying lengths and sequences. An in vitro system for protein synthesis assembled from purified Escherichia coli components was used to produce RNCs stalled on truncated mRNAs. The affinity of TF to RNCs exposing RNA polymerase sequences increased with the length of the nascent peptides. TF bound to RNA polymerase RNCs with significantly higher affinity than to inner membrane protein leader peptidase and bacterioopsin RNCs. The latter two RNCs are substrates for signal recognition particle, suggesting complementary affinities of TF and signal recognition particle to nascent peptides targeted for cytoplasm and membrane.

  • 30. Razafimahefa, Solofoniaina
    et al.
    Mutulis, Felikss
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mutule, Ilze
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Liepinsh, Edvards
    Dambrova, Maija
    Cirule, Helena
    Svalbe, Baiba
    Yahorava, Sviatlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yahorau, Aleh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rasolondratovo, Benoit
    Rasoanaivo, Philippe
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Libiguins A and B: Novel Phragmalin Limonoids Isolated from Neobeguea mahafalensis Causing Profound Enhancement of Sexual Activity2014Inngår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, nr 4, s. 306-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a screening programme directed towards the discovery of drugs that could enhance sexual activity, we found that a decoction of the root bark of Neobeguea mahafalensis displayed an extraordinarily high potency and remarkably long duration in augmenting sexual activity in male rodents. Bioassay-guided fractionation led to the isolation of two pharmacoactive constituents, which turned out to be novel 1,8,9-orthoacetate phragmalin limonoids that we named libiguins A and B, each with a C-16/30 -lactone ring. Chemical structures were established by the interpretation of their 1D and 2DNMR data. In vivo pharmacological tests showed that starting with a treatment from 0.004-0.4mg/kg/day for three consecutive days, over a 3-h sampling period, these limonoids induced a long-lasting augmentation of frequency and sustainment of mounting behaviour in male rodents, with an effect lasting for up to 11 days post-treatment. Libiguin A proved to be markedly more potent than libiguin B. This report is the first of limonoids having such an effect, and the findings could lead to novel therapies for the treatment of sexual dysfunction. Moreover, the results can serve as an opening to elucidate the central physiological control of mating behaviour, which is still not well mapped out.

  • 31.
    Shoombuatong, Watshara
    et al.
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Nabu, Sunanta
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Simeon, Saw
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Prachayasittikul, Virapong
    Mahidol Univ, Fac Med Technol, Dept Clin Microbiol & Appl Technol, Bangkok 10700, Thailand..
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Extending proteochemometric modeling for unraveling the sorption behavior of compound-soil interaction2016Inngår i: Chemometrics and Intelligent Laboratory Systems, ISSN 0169-7439, E-ISSN 1873-3239, Vol. 151, s. 219-227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Contamination of ground water by industrial chemicals presents a major environmental and health problem. Soil sorption plays an important role in the transport and movement of such pollutant chemicals. In this study, proteochemometric (PCM) modeling was used to unravel the origins of interactions of 17 phthalic acid esters (PAEs) against 3 soil types by predicting the organic carbon content normalized sorption coefficient (logK(oc)) values as a function of fingerprint descriptors of 17 PAEs and physical and textural properties of 3 soils. The results showed that PCM models provided excellent predictivity (R-2 = 0.94, Q(2) = 0.89,Q(Ext)(2) = 0.85). In further validation of the model, our proposed PCM model was assessed by leave-one-compound-out (Q(LOCO)(2) = 0.86) and leave-one-soil-out (Q(LOCO)(2) = 0.86) cross-validations. The transparency of the PCM model allowed interpretation of the underlying importance of descriptors, which potentially contributes to a better understanding on the outcome of PAEs in the environment. A thorough analysis of descriptor importance revealed the contribution of secondary carbon atoms on the hydrophobicity and flexibility of PAEs as significant properties in influencing the soil sorption capacity.

  • 32. Shoombuatong, Watshara
    et al.
    Prathipati, Philip
    Prachayasittikul, Veda
    Schaduangrat, Nalini
    Malik, Aijaz Ahmad
    Pratiwi, Reny
    Wanwimolruk, Sompon
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gleeson, Matthew Paul
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Towards Predicting the Cytochrome P450 Modulation: From QSAR to proteochemometric modeling.2017Inngår i: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Vol. 18, nr 6, s. 540-555Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug metabolism determines the fate of a drug when it enters the human body and is a critical factor in defining their absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Among the various drug metabolizing enzymes, cytochrome P450s (CYP450) constitute an important protein family that aside from functioning in xenobiotic metabolism is also responsible for a diverse array of other roles encompassing steroid and cholesterol biosynthesis, fatty acid metabolism, calcium homeostasis, neuroendocrine functions and growth regulation. Although CYP450 typically convert xenobiotics into safe metabolites, there are some situations whereby the metabolite is more toxic than its parent molecule. Computational modeling has been instrumental in CYP450 research by rationalizing the nature of the binding event (i.e. inhibit or induce CYP450s) or metabolic stability of query compounds of interest. A plethora of computational approaches encompassing ligand, structure and systems based approaches have been utilized to model CYP450-ligand interactions. This review provides a brief background on the CYP450 family (i.e. its roles, advantages and disadvantages as well as its modulators) and then discusses the various computational approaches that have been used to model CYP450-ligand interaction. Particular focus is given to the use of quantitative structure-activity relationship (QSAR) and more recent proteochemometric modeling studies. Finally, a perspective on the current state of the art and future trends of the field is provided.

  • 33.
    Shutava, Iryna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapinsh, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Melanocortin 4 receptor in silico mutagenesis and docking studies2013Inngår i: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 42, s. S75-S75Artikkel i tidsskrift (Annet vitenskapelig)
  • 34.
    Simeon, Saw
    et al.
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand.;Kasetsart Univ, Fac Sci, Interdisciplinary Grad Program Biosci, Bangkok 10900, Thailand..
    Li, Hao
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Win, Thet Su
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Malik, Aijaz Ahmad
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Kandhro, Abdul Hafeez
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand.;Mahidol Univ, Ctr Res & Innovat, Fac Med Technol, Bangkok 10700, Thailand..
    Piacham, Theeraphon
    Mahidol Univ, Dept Clin Microbiol & Appl Technol, Fac Med Technol, Bangkok 10700, Thailand..
    Shoombuatong, Watshara
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Nuchnoi, Pornlada
    Mahidol Univ, Ctr Res & Innovat, Fac Med Technol, Bangkok 10700, Thailand..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gleeson, M. Paul
    King Mongkuts Inst Technol Ladkrabang, Dept Biomed Engn, Fac Engn, Bangkok 10520, Thailand..
    Nantasenamat, Chanin
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    PepBio: predicting the bioactivity of host defense peptides2017Inngår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, nr 56, s. 35119-35134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Host defense peptides (HDPs) represents a class of ubiquitous and rapid responding immune molecules capable of direct inactivation of a wide range of pathogens. Recent research has shown HDPs to be promising candidates for development as a novel class of broad-spectrum chemotherapeutic agent that is effective against both pathogenic microbes and malignant neoplasm. This study aims to quantitatively explore the relationship between easy-to-interpret amino acid composition descriptors of HDPs with their respective bioactivities. Classification models were constructed using the C4.5 decision tree and random forest classifiers. Good predictive performance was achieved as deduced from the accuracy, sensitivity and specificity in excess of 90% and Matthews correlation coefficient in excess of 0.5 for all three evaluated data subsets (e.g. training, 10-fold cross-validation and external validation sets). The source code and data set used for the construction of classification models are available on GitHub at https://github.com/chaninn/pepbio/.

  • 35.
    Simeon, Saw
    et al.
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Shoombuatong, Watshara
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Anuwongcharoen, Nuttapat
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    Preeyanon, Likit
    Mahidol Univ, Fac Med Technol, Dept Community Med Technol, Bangkok 10700, Thailand..
    Prachayasittikul, Virapong
    Mahidol Univ, Fac Med Technol, Dept Community Med Technol, Bangkok 10700, Thailand..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok 10700, Thailand..
    osFP: a web server for predicting the oligomeric states of fluorescent proteins2016Inngår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, artikkel-id 72Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Currently, monomeric fluorescent proteins (FP) are ideal markers for protein tagging. The prediction of oligomeric states is helpful for enhancing live biomedical imaging. Computational prediction of FP oligomeric states can accelerate the effort of protein engineering efforts of creating monomeric FPs. To the best of our knowledge, this study represents the first computational model for predicting and analyzing FP oligomerization directly from the amino acid sequence. Results: After data curation, an exhaustive data set consisting of 397 non-redundant FP oligomeric states was compiled from the literature. Results from benchmarking of the protein descriptors revealed that the model built with amino acid composition descriptors was the top performing model with accuracy, sensitivity and specificity in excess of 80% and MCC greater than 0.6 for all three data subsets (e.g. training, tenfold cross-validation and external sets). The model provided insights on the important residues governing the oligomerization of FP. To maximize the benefit of the generated predictive model, it was implemented as a web server under the R programming environment. Conclusion: osFP affords a user-friendly interface that can be used to predict the oligomeric state of FP using the protein sequence. The advantage of osFP is that it is platform-independent meaning that it can be accessed via a web browser on any operating system and device. osFP is freely accessible at http://codes.bio/osfp/ while the source code and data set is provided on GitHub at https://github.com/chaninn/osFP/.

  • 36. Simeon, Saw
    et al.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nabu, Sunanta
    Anuwongcharoen, Nuttapat
    Prachayasittikul, Virapong
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Origin of aromatase inhibitory activity via proteochemometric modeling2016Inngår i: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 4, artikkel-id e1979Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents.

  • 37.
    Spjuth, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Junaid, Muhammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Services for prediction of drug susceptibility for HIV proteases and reverse transcriptases at the HIV Drug Research Centre2011Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 27, nr 12, s. 1719-1720Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Summary: The HIV Drug Research Centre (HIVDRC) has established Web services for prediction of drug susceptibility for HIV proteases and reverse transcriptases. The services are based on two proteochemometric models which accepts a protease or reverse transcriptase sequence in amino acid form, and outputs the predicted drug susceptibility values. The predictions are based on a comprehensive analysis where all the relevant inhibitors are included, resulting in models with excellent predictive capabilities.

    Availability and Implementation: The services are implemented as interoperable Web services (REST and XMPP), with supporting web pages to allow for individual analyses. A set of plugins were also developed which make the services available from the Bioclipse workbench for life science. Services are available athttp://www.hivdrc.org/services.

  • 38.
    Spjuth, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Georgiev, Valentin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Carlsson, Lars
    Global Safety Assesment, AstraZeneca R&D.
    Alvarsson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Berg, Arvid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Willighagen, Egon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bioclipse-R: Integrating management and visualization of life science data with statistical analysis2013Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 29, nr 2, s. 286-289Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bioclipse, a graphical workbench for the life sciences, provides functionality for managing and visualizing life science data. We introduce Bioclipse-R, which integrates Bioclipse and the statistical programming language R. The synergy between Bioclipse and R is demonstrated by the construction of a decision support system for anticancer drug screening and mutagenicity prediction, which shows how Bioclipse-R can be used to perform complex tasks from within a single software system.

  • 39.
    Strömbergsson, Helena
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kleywegt, Gerard J.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturell molekylärbiologi.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Towards proteome-wide interaction models using the proteochemometrics approach2010Inngår i: Molecular Informatics, ISSN 1868-1743, Vol. 29, nr 6-7, s. 499-508Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A proteochemometrics model was induced from all interaction data in the BindingDB database, comprizing in all 7078 protein-ligand complexes with representatives from all major drug target categories. Proteins were represented by alignment-independent sequence descriptors holding information on properties such as hydrophobicity, charge, and secondary structure. Ligands were represented by commonly used QSAR descriptors. The inhibition constant (pK(i)) values of protein-ligand complexes were discretized into "high" and "low" interaction activity. Different machine-learning techniques were used to induce models relating protein and ligand properties to the interaction activity. The best was decision trees, which gave an accuracy of 80% and an area under the ROC curve of 0.81. The tree pointed to the protein and ligand properties, which are relevant for the interaction. As the approach does neither require alignments nor knowledge of protein 3D structures virtually all available protein-ligand interaction data could be utilized, thus opening a way to completely general interaction models that may span entire proteomes.

  • 40.
    Svennebring, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Net present value approaches for drug discovery2013Inngår i: SpringerPlus, E-ISSN 2193-1801, Vol. 2, artikkel-id 140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Three dedicated approaches to the calculation of the risk-adjusted net present value (rNPV) in drug discovery projects under different assumptions are suggested. The probability of finding a candidate drug suitable for clinical development and the time to the initiation of the clinical development is assumed to be flexible in contrast to the previously used models. The rNPV of the post-discovery cash flows is calculated as the probability weighted average of the rNPV at each potential time of initiation of clinical development. Practical considerations how to set probability rates, in particular during the initiation and termination of a project is discussed.

  • 41.
    Uhlen, S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Muceniece, R
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rangel, N
    Tiger, G
    Wikberg, J E
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Comparison of the binding activities of some drugs on alpha 2A, alpha 2B and alpha 2C-adrenoceptors and non-adrenergic imidazoline sites in the guinea pig.1995Inngår i: Pharmacol Toxicol, ISSN 0901-9928, Vol. 76, nr 6, s. 353-64Artikkel i tidsskrift (Fagfellevurdert)
  • 42.
    Wikberg, J E
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hudson, A L
    A series of novel imidazoline I2-receptor selective Schiff bases of 1-(benzylidenamino)-3,3-dimethylguanidine.1997Inngår i: Neurochem Int, ISSN 0197-0186, Vol. 30, nr 1, s. 95-9Artikkel i tidsskrift (Fagfellevurdert)
  • 43.
    Wikberg, Jarl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Willighagen, Egon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engkvist, Ola
    AstraZeneca R&D, Sweden.
    Alvarsson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Introduction to Pharmaceutical Bioinformatics2010 (oppl. 2)Bok (Annet vitenskapelig)
  • 44.
    Willighagen, Egon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alvarsson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Annsofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lampa, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lapins, Maris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Linking the Resource Description Framework to cheminformatics and proteochemometrics2011Inngår i: Journal of Biomedical Semantics, ISSN 2041-1480, E-ISSN 2041-1480, Vol. 2, nr Suppl 1, s. 6-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND :

    Semantic web technologies are finding their way into the life sciences. Ontologies and semantic markup have already been used for more than a decade in molecular sciences, but have not found widespread use yet. The semantic web technology Resource Description Framework (RDF) and related methods show to be sufficiently versatile to change that situation.

    RESULTS :

    The work presented here focuses on linking RDF approaches to existing molecular chemometrics fields, including cheminformatics, QSAR modeling and proteochemometrics. Applications are presented that link RDF technologies to methods from statistics and cheminformatics, including data aggregation, visualization, chemical identification, and property prediction. They demonstrate how this can be done using various existing RDF standards and cheminformatics libraries. For example, we show how IC50 and Ki values are modeled for a number of biological targets using data from the ChEMBL database.

    CONCLUSIONS :

    We have shown that existing RDF standards can suitably be integrated into existing molecular chemometrics methods. Platforms that unite these technologies, like Bioclipse, makes this even simpler and more transparent. Being able to create and share workflows that integrate data aggregation and analysis (visual and statistical) is beneficial to interoperability and reproducibility. The current work shows that RDF approaches are sufficiently powerful to support molecular chemometrics workflows.

  • 45.
    Willighagen, Egon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Linking Open Drug Data to Cheminformatics and Proteochemometrics2010Inngår i: SWAT4LS-2009 - Semantic Web Applications and Tools for Life Sciences: Proceedings of the Workshop on Semantic Web Applications and Tools for Life Sciences, Amsterdam, The Netherlands, November 20, 2009. / [ed] M. Scott Marshall, Albert Burger, Paolo Romano, Adrian Paschke, and Andrea Splendiani, Aachen, Germany: Sun SITE Central Europe , 2010Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Semantic Web technologies have made great steps forwardin data exchange in health care and life sciences in the past years. Thework presented here focuses to a some extent on making drug discoveryrelated data available as RDF, and even more so on the integration ofRDF approaches with data analysis of molecular information in drugdiscovery fields like cheminformatics and proteochemometrics. We hereshow how the chem- and bioinformatics workbench Bioclipse and theChemistry Development Kit can be used to this purpose.Abstract. Semantic Web technologies have made great steps forwardin data exchange in health care and life sciences in the past years. Thework presented here focuses to a some extent on making drug discoveryrelated data available as RDF, and even more so on the integration ofRDF approaches with data analysis of molecular information in drugdiscovery fields like cheminformatics and proteochemometrics. We hereshow how the chem- and bioinformatics workbench Bioclipse and theChemistry Development Kit can be used to this purpose.

  • 46.
    Win, Thet Su
    et al.
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand.;Univ Med Technol, Dept Med Lab Technol, Yangon 11012, Myanmar..
    Malik, Aijaz Ahmad
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Prachayasittikul, Virapong
    Mahidol Univ, Dept Clin Microbiol & Appl Technol, Fac Med Technol, Bangkok 10700, Thailand..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nantasenamat, Chanin
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    Shoombuatong, Watshara
    Mahidol Univ, Ctr Data Min & Biomed Informat, Fac Med Technol, Bangkok 10700, Thailand..
    HemoPred: a web server for predicting the hemolytic activity of peptides2017Inngår i: Future Medicinal Chemistry, ISSN 1756-8919, E-ISSN 1756-8927, Vol. 9, nr 3, s. 275-291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Toxicity arising from hemolytic activity of peptides hinders its further progress as drug candidates. Materials & methods: This study describes a sequence-based predictor based on a random forest classifier using amino acid composition, dipeptide composition and physicochemical descriptors (named HemoPred). Results: This approach could outperform previously reported method and typical classification methods (e.g., support vector machine and decision tree) verified by fivefold cross-validation and external validation with accuracy and Matthews correlation coefficient in excess of 95% and 0.91, respectively. Results revealed the importance of hydrophobic and Cys residues on alpha-helix and beta-sheet, respectively, on the hemolytic activity. Conclusion: A sequence-based predictor which is publicly available as the web service of HemoPred, is proposed to predict and analyze the hemolytic activity of peptides.

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