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  • 1.
    Diwakarla, Shanti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reddy Vanga, Sudarsana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Shamsudin Khan, Yasmin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Ng, Leelee
    Pham, Vi
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundback, Thomas
    Jenmalm-Jensen, Annika
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Yeen Chai, Siew
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density2016In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed)
    Abstract [en]

    Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

  • 2.
    Reddy Vanga, Sudarsana
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Ng, Leelee
    Monash Univ, Biomed Discovery Inst, Dept Physiol, Clayton, Vic 3800, Australia.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Chai, Siew Yeen
    Monash Univ, Biomed Discovery Inst, Dept Physiol, Clayton, Vic 3800, Australia.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides2018In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.

  • 3.
    Vanga, Sudarsana Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Probing Ligand Binding Mechanisms in Insulin-Regulated Aminopeptidases: Computational analysis and free energy calculations of binding modes2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In recent years insulin-regulated aminopeptidase (IRAP) has emerged as a new therapeutic target for the treatment of Alzheimer’s disease and other memory-related disorders. So far, many potent and specific IRAP inhibitors had been disclosed, including peptides, peptidomimetics, and low-molecular-weight sulfonamides. In this thesis, various computational approaches such as docking, molecular dynamics (MD), linear interaction energy (LIE), and free energy perturbations (FEP) are used to understand the molecular basis for the binding of these inhibitors to the IRAP.

    By applying MD and LIE, the binding mode of Ang IV and the critical role of its N-terminal tripeptide in the binding to IRAP were described. The stark difference in the binding properties of two stereoisomers of a peptidomimetic inhibitor, HA08 and HA09, was determined using MD simulations and LIE binding affinity estimations. With the help of the FEP method, we discriminate the most probable, between two alternative binding poses for the sulfonamide family of compounds. The binding modes of the HFI family of compounds (competitive inhibitors), and spiro-oxindole compounds (allosteric, uncompetitive inhibitors) were also proposed utilizing a combination of related computational approaches. In this thesis, the specificity of the diverse class of inhibitors and substrates (oxytocin and vasopressin) for IRAP compared to other M1 aminopetidase family members was disclosed as a result of the unique Gly-Ala-Met-Glu-Asn (GAMEN) loop orientation. The different studies performed along this thesis resulted in several proposed binding modes, which were evaluated by different free energy calculation approaches, namely LIE and FEP methods. In all cases, the calculated free energies are in excellent agreement with the experimental data, which strongly supports the final binding models here proposed.

    These results of this thesis will be useful in future lead generation and optimization process and hopefully in the development of better cognitive enhancers for the treatment of dementia and other related diseases such as Alzheimer’s disease.

  • 4.
    Vanga, Sudarsana Reddy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-based InhibitorsManuscript (preprint) (Other academic)
    Abstract [en]

    Inhibition of the insulin-regulated aminopeptidase (IRAP) improves memory and cognition in animal models. The enzyme has been recently crystallized and several series of inhibitors reported. We herein focused on one series of benzopyran-based inhibitors of IRAP, known as HFI series, and developed a robust computational model to explain the SAR and potentially guide the optimization of this scaffold. Our binding model positions the benzopyran ring in the catalytic binding site, coordinating the Zn+2 ion through the oxygen in position 3 of the, in contrast to previous hypothesis. The whole series of HFI compounds was systematically simulated using molecular dynamics in this binding orientation and binding affinity estimated with the linear interaction energy (LIE) method. The agreement with experimental affinities supports the binding mode proposed, which was further challenged by rigorous free energy perturbation calculations. Here, we found excellent correlation between experimental and calculated binding affinity differences, both between selected compound pairs and also for recently reported experimental data concerning the site directed mutagenesis of residue Phe544. The computationally derived structure-activity relationship of the HFI series and the demonstrated involvement of Phe544 in the binding of this scaffold provide valuable information for further lead optimization of novel IRAP inhibitors.

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