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    3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors

    Access Status
    Open access via publisher
    Authors
    Arooj, Mahreen
    Thangapandian, S.
    John, S.
    Hwang, S.
    Park, J.
    Lee, K.
    Date
    2011
    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. 2011. 3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors. International Journal of Molecular Sciences. 12 (12): pp. 9236-9264.
    Source Title
    International Journal of Molecular Sciences
    DOI
    10.3390/ijms12129236
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/18615
    Collection
    • Curtin Research Publications
    Abstract

    Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating "Hypo1", it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC 50) data thus successfully validating "Hypo1" by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

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