title: 3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors.
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.
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science(RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Korea. mahr@bio.gnu.ac.kr
authors.forename: Mahreen
authors.initials: M
authors.lastname: Arooj
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Shalini
authors.initials: S
authors.lastname: John
authors.forename: Swan
authors.initials: S
authors.lastname: Hwang
authors.forename: Jong Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015842:Serine Proteinase Inhibitors; D053818:Chymases