Identification of dual Acetyl-CoA carboxylases 1 and 2 inhibitors by pharmacophore based virtual screening and molecular docking approach.

Abstract

Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme that plays a vital role in obesity-induced type 2 diabetes and fatty acid metabolism. To identify dual inhibitors of Acetyl-CoA carboxylase1 and Acetyl-CoA carboxylase2, a pharmacophore modelling approach has been employed. The best HypoGen pharmacophore model for ACC2 inhibitors (Hypo1_ACC2) consists of one hydrogen bond acceptor, one hydrophobic aliphatic and one hydrophobic aromatic feature, whereas the best pharmacophore (Hypo1_ACC1) for ACC1 consists of one additional hydrogen-bond donor (HBD) features. The best pharmacophore hypotheses were validated by various methods such as test set, decoy set and Cat-Scramble methodology. The validated pharmacophore models were used to screen several small-molecule databases, including Specs, NCI, ChemDiv and Natural product databases to identify the potential dual ACC inhibitors. The virtual hits were then subjected to several filters such as estimated [Formula: see text] value, quantitative estimation of drug-likeness and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as potential starting points for the design of novel dual ACC inhibitors.

• Authors: Anuseema Bhadauriya, Gaurao V Dhoke, Rahul P Gangwal, Mangesh V Damre, Abhay T Sangamwar
• Journal: Molecular diversity (Mol Divers) Vol. 17 Issue 1 Pg. 139-49 (Feb 2013) ISSN: 1573-501X [Electronic] Netherlands
• PMID: 23334436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (antagonists & inhibitors)
• Computer Simulation
• Drug Design
• Drug Evaluation, Preclinical
• Hydrophobic and Hydrophilic Interactions
• Models, Chemical
• Models, Molecular
• Molecular Docking Simulation
• Molecular Structure
• Obesity (drug therapy)
• Structure-Activity Relationship