Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 12, Issue 12, Pages 9236-9264Publisher
MDPI AG
DOI: 10.3390/ijms12129236
Keywords
chymase; pharmacophore; molecular docking; in silico screening; density functional theory; molecular electrostatic potential
Funding
- Basic Science Research Program [2009-0073267]
- Pioneer Research Center Program [2009-0081539]
- National Research Foundation of Korea (NRF) [2010-0029084]
- Ministry of Education, Science and Technology (MEST) of Republic of Korea
- Rural Development Administration (RDA) of Republic of Korea [PJ008038]
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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 (IC50) 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.
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