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3D-QSAR studies of quinoline Schiff bases as enoyl acyl carrier protein reductase inhibitors

Authors Joshi S, Dixit S, More U, Kumar D, Aminabhavi T, Kulkarni V

Received 30 June 2014

Accepted for publication 3 September 2014

Published 29 November 2014 Volume 2014:4 Pages 59—75


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Xing-Cong Li

Shrinivas D Joshi, Sheshagiri R Dixit, Uttam A More, Devendra Kumar, Tejraj M Aminabhavi, Venkatrao H Kulkarni

Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, SET's College of Pharmacy, Sangolli Rayanna Nagar, Karnataka, India

Abstract: Nicotinamide adenine dinucleotide reduced-dependent reduction of trans-2-enoyl acyl carrier protein (ACP) to yield nicotinamide adenine dinucleotide (NAD+) and reduced enoyl thioester-ACP substrate is catalyzed by the enoyl-ACP reductase (ENR) enzyme which is an important enzyme for type II fatty acid synthesis (FAS-II) (PubMed identifier 15139852). It is also a useful object for the discovery of antimicrobial drugs because of its fundamental role in the metabolism. Hence, inhibition of ENR might be a novel approach in developing antitubercular (anti-TB) drugs. Quinolines are the important class of heterocycles found in natural and synthetic products of various kinds. In this paper, docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) (comparative molecular field analysis [CoMFA], comparative molecular similarity indices analysis [CoMSIA], and Topomer CoMFA) studies were performed on a set of quinoline hydrazones. According to docking studies, active site of the enzyme, amino acid residue TYR158, and co-factor NAD+ are important in binding with the ligand. Of all the compounds tested, compounds 45 and 46 have shown a docking score of 6.22, while compound 26 has a docking score of 6.09. The CoMFA model with steric and electrostatic field exhibited q2=0.617, r2=0.81; CoMSIA model displayed q2=0.631, r2=0.755; Topomer CoMFA model exhibited q2=0.644, r2=0.865 with a standard error of estimate (SEE) of 0.37. The docking results provided detailed structurally important binding features between quinoline hydrazones and the ENR enzyme. Our findings also provide useful hints and information for designing compounds with improved inhibitory activity.

Keywords: quinoline hydrazones, enoyl-ACP reductase, docking, QSAR: CoMFA, CoMSIA, Topomer CoMFA

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