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DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. (T. Alwyn Jones, Sherry L. Mowbray)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Anders Karlèn, Mats Larhed)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. (T. Alwyn Jones, Sherry L. Mowbray)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Anders Karlèn, Mats Larhed)
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 15, 6190-6199 p.Article in journal (Refereed) Published
Abstract [en]

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.

Place, publisher, year, edition, pages
2013. Vol. 56, no 15, 6190-6199 p.
Keyword [en]
Mycobacterium tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR
National Category
Structural Biology
Research subject
Biology with specialization in Structural Biology; Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-196616DOI: 10.1021/jm4006498ISI: 000323082400015OAI: oai:DiVA.org:uu-196616DiVA: diva2:610506
Funder
Swedish Foundation for Strategic Research Swedish Research Council
Note

De tre (3) första författarna delar förstaförfattarskapet.

Available from: 2013-03-11 Created: 2013-03-11 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Targeting Infectious Disease: Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis
Open this publication in new window or tab >>Targeting Infectious Disease: Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The recent emergence of a number of new viral diseases as well as the re-emergence of tuberculosis (TB), indicate an urgent need for new drugs against viral and bacterial infections.

Coronavirus nsp1 has been shown to induce suppression of host gene expression and interfere with host immune response. However, the mechanism behind this is currently unknown. Here we present the first nsp1 structure from an alphacoronavirus, Transmissible gastroenteritis virus (TGEV) nsp1. Contrary to previous speculation, the TGEV nsp1 structure clearly shows that alpha- and betacoronavirus nsp1s have a common evolutionary origin. However, differences in conservation, shape and surface electrostatics indicate that the mechanism for nsp1-induced suppression of host mRNA translation is likely to be different in the alpha- and betacoronavirus genera.

The Modoc virus is a neuroinvasive rodent virus with similar pathology as flavivirus encephalitis in humans. The flaviviral methyltransferase catalyses the two methylations required to complete 5´ mRNA capping, essential for mRNA stability and translation. The structure of the Modoc NS5 methyltransferase domain was determined in complex with its cofactor S-adenosyl-L-methionine. The observed methyltransferase conservation between Modoc and other flaviviral branches, indicates that it may be possible to identify drugs that target a range of flaviviruses and supports the use of Modoc virus as a model for general flaviviral studies.

1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is part of the methylerythritol phosphate (MEP) pathway that produces essential precursors for isoprenoid biosynthesis. This pathway is used by a number of pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, but it is not present in humans. Using a structure-based approach, we designed a number of MtDXR inhibitors, including a novel fosmidomycin-analogue that exhibited improved activity against P.falciparum in an in vitro blood cell growth assay. The approach also allowed the first design of an inhibitor that bridge both DXR substrate and co-factor binding sites, providing a stepping-stone for further optimization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1028
Keyword
RNA virus, coronavirus, alphacoronavirus, nsp1, TGEV, flavivirus, Modoc virus, NS5, methyltransferase, mRNA capping, Mycobacterium tuberculosis, tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR, fosmidomycin analogues, MEP pathway, drug development, xray-crystallography
National Category
Structural Biology Biochemistry and Molecular Biology
Research subject
Biology with specialization in Structural Biology; Biology with specialization in Molecular Biology; Biochemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-196623 (URN)978-91-554-8618-1 (ISBN)
Public defence
2013-04-26, B42, Biomedical Center, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research
Available from: 2013-04-05 Created: 2013-03-11 Last updated: 2013-08-30Bibliographically approved
2. Computational Modelling in Drug Discovery: Application of Structure-Based Drug Design, Conformal Prediction and Evaluation of Virtual Screening
Open this publication in new window or tab >>Computational Modelling in Drug Discovery: Application of Structure-Based Drug Design, Conformal Prediction and Evaluation of Virtual Screening
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Structure-based drug design and virtual screening are areas of computational medicinal chemistry that use 3D models of target proteins. It is important to develop better methods in this field with the aim of increasing the speed and quality of early stage drug discovery.

The first part of this thesis focuses on the application of structure-based drug design in the search for inhibitors for the protein 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), one of the enzymes in the DOXP/MEP synthetic pathway. This pathway is found in many bacteria (such as Mycobacterium tuberculosis) and in the parasite Plasmodium falciparum.

In order to evaluate and improve current virtual screening methods, a benchmarking data set was constructed using publically available high-throughput screening data. The exercise highlighted a number of problems with current data sets as well as with the use of publically available high-throughput screening data. We hope this work will help guide further development of well designed benchmarking data sets for virtual screening methods.

Conformal prediction is a new method in the computer-aided drug design toolbox that gives the prediction range at a specified level of confidence for each compound. To demonstrate the versatility and applicability of this method we derived models of skin permeability using two different machine learning methods; random forest and support vector machines.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 235
Keyword
drug discovery, docking, virtual screening, tuberculosis, conformal prediction
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-328505 (URN)978-91-513-0049-8 (ISBN)
Public defence
2017-10-13, B/B42, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2017-09-21 Created: 2017-08-24 Last updated: 2017-10-17

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