title: Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations.
abstract: Acetyl-CoA carboxylase (ACC) enzyme plays an important role in the regulation of biosynthesis and oxidation of fatty acids. ACC is a recognized drug target for the treatment of obesity and diabetes. Combination of ligand and structure-based in silico methods along with activity and toxicity prediction provides best lead compounds in the drug discovery process. In this study, a data-set of 100 ACC inhibitors were used for the development of comparative molecular field analysis (CoMFA) and comparative molecular similarity index matrix analysis (CoMSIA) models. The generated contour maps were used for the design of novel ACC inhibitors. CoMFA and CoMSIA models were used for the predication of activity of designed compounds. In silico toxicity risk prediction study was carried out for the designed compounds. Molecular docking and dynamic simulations studies were performed to know the binding mode of designed compounds with the ACC enzyme. The designed compounds showed interactions with key amino acid residues important for catalysis, and good correlation was observed between binding free energy and inhibition of ACC.
authors.affiliation: a Department of Pharmaceutical Chemistry, Institute of Pharmacy , Nirma University , Ahmedabad 382481 , Gujarat , India.
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Vyas
authors.affiliation: a Department of Pharmaceutical Chemistry, Institute of Pharmacy , Nirma University , Ahmedabad 382481 , Gujarat , India.
authors.forename: Mohini
authors.initials: M
authors.lastname: Dabasia
authors.affiliation: a Department of Pharmaceutical Chemistry, Institute of Pharmacy , Nirma University , Ahmedabad 382481 , Gujarat , India.
authors.forename: Gulamnizami
authors.initials: G
authors.lastname: Qureshi
authors.affiliation: b Institute of Science, Nirma University , S.G. Highway, Chharodi, Ahmedabad 382481 , Gujarat , India.
authors.forename: Palak
authors.initials: P
authors.lastname: Patel
authors.affiliation: a Department of Pharmaceutical Chemistry, Institute of Pharmacy , Nirma University , Ahmedabad 382481 , Gujarat , India.
authors.forename: Manjunath
authors.initials: M
authors.lastname: Ghate
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000103:Acetyl-CoA Carboxylase
keywords: ACC inhibitors; CoMFA and CoMSIA; molecular docking; molecular dynamic simulations