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    A Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors

    196150_105696_79329.pdf (2.149Mb)
    Access Status
    Open access
    Authors
    Arooj, Mahreen
    Sakkiah, Sugunadevi
    Kim, Songmi
    Arulalapperumal, Venkatesh
    Woo Lee, Keun
    Date
    2013
    Type
    Journal Article
    
    Metadata
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    Citation
    Arooj, Mahreen and Sakkiah, Sugunadevi and Kim, Songmi and Arulalapperumal, Venkatesh and Woo Lee, Keun. 2013. A Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors. PLoS ONE. 8 (4): e63030.
    Source Title
    PLoS ONE
    DOI
    10.1371/journal.pone.0063030
    ISSN
    19326203
    Remarks

    This article is published under the Open Access publishing model and distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/ Please refer to the licence to obtain terms for any further reuse or distribution of this work.

    URI
    http://hdl.handle.net/20.500.11937/18968
    Collection
    • Curtin Research Publications
    Abstract

    Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure–based pharmacophore models. One ligand–based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well.

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