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    Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition

    Access Status
    Open access via publisher
    Authors
    Arooj, Mahreen
    Thangapandian, S.
    John, S.
    Hwang, S.
    Park, J.
    Lee, K.
    Date
    2012
    Type
    Journal Article
    
    Metadata
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    Citation
    Arooj, M. and Thangapandian, S. and John, S. and Hwang, S. and Park, J. and Lee, K. 2012. Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition. Chemical Biology and Drug Design. 80 (6): pp. 862-875.
    Source Title
    Chemical Biology and Drug Design
    DOI
    10.1111/cbdd.12006
    ISSN
    1747-0277
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/41921
    Collection
    • Curtin Research Publications
    Abstract

    To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4-diazepane-2,5-diones ring are essential for effective binding of inhibitors at active site of enzyme. The Bayesian model with receiver operating curve statistic of 0.82 also identified arylsulfonyl and aminocarbonyl as the molecular features favoring and not favoring inhibition of chymase, respectively. Moreover, genetic function approximation was applied to construct 3D quantitative structure-activity relationships models. Two models (genetic function approximation model 1 r2=0.812 and genetic function approximation model 2 r2=0.783) performed better in terms of correlation coefficients and cross-validation analysis. In general, this study is used as example to illustrate how combinational use of 2D/3D quantitative structure-activity relationships modeling techniques, molecular docking, frontier molecular orbital density fields (highest occupied molecular orbital and lowest unoccupied molecular orbital), and molecular electrostatic potential analysis may be useful to gain an insight into the binding mechanism between enzyme and its inhibitors. 2D and 3D QSAR models have been developed for chymase and its novel 1,4-diazepane-2,5-diones inhibitors which explore the origin of inhibitory activity and crucial molecular features contributing to binding specificity. The DFT method was used to optimize molecular structures with the subsequent analysis of HOMO, LUMO, and molecular electrostatic potential (MEP) maps which revealed negative potentials near 1,4-diazepane-2,5-diones ring are essential for effective binding of inhibitors at active site of enzyme. © 2012 John Wiley & Sons A/S.

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