title: Computational studies of novel chymase inhibitors against cardiovascular and allergic diseases: mechanism and inhibition.
abstract: To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4-diazepane-2,5-diones ring are essential for effective binding of inhibitors at active site of enzyme. The Bayesian model with receiver operating curve statistic of 0.82 also identified arylsulfonyl and aminocarbonyl as the molecular features favoring and not favoring inhibition of chymase, respectively. Moreover, genetic function approximation was applied to construct 3D quantitative structure-activity relationships models. Two models (genetic function approximation model 1 r(2) = 0.812 and genetic function approximation model 2 r(2) = 0.783) performed better in terms of correlation coefficients and cross-validation analysis. In general, this study is used as example to illustrate how combinational use of 2D/3D quantitative structure-activity relationships modeling techniques, molecular docking, frontier molecular orbital density fields (highest occupied molecular orbital and lowest unoccupied molecular orbital), and molecular electrostatic potential analysis may be useful to gain an insight into the binding mechanism between enzyme and its inhibitors.
authors: 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, Gazha-dong, Jinju, 660-701 Korea.
authors: Mahreen
authors: M
authors: Arooj
authors: Sundarapandian
authors: S
authors: Thangapandian
authors: Shalini
authors: S
authors: John
authors: Swan
authors: S
authors: Hwang
authors: Jong K
authors: JK
authors: Park
authors: Keun W
authors: KW
authors: Lee
mesh_terms: D001381:Azepines / Q000737:chemistry; D001499:Bayes Theorem; D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000188:drug therapy; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D055672:Static Electricity
chemical_list: C545228:1,4-diazepane; D001381:Azepines; D011480:Protease Inhibitors; D053818:Chymases