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dc.contributor.authorArooj, Mahreen
dc.contributor.authorSakkiah, Sugunadevi
dc.contributor.authorKim, Songmi
dc.contributor.authorArulalapperumal, Venkatesh
dc.contributor.authorWoo Lee, Keun
dc.identifier.citationArooj, 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.

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.

dc.publisherPublic Library of Science
dc.titleA Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors
dc.typeJournal Article
dcterms.source.titlePLoS ONE

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

curtin.accessStatusOpen access

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