QSAR and Molecular Docking Studies of Oxadiazole-Ligated Pyrrole Derivatives as Enoyl-ACP (CoA) Reductase Inhibitors

Kalyani D Asgaonkar

doi:10.3797/scipharm.1310-05

Abstract

A quantitative structure-activity relationship model was developed on a series of compounds containing oxadiazole-ligated pyrrole pharmacophore to identify key structural fragments required for anti-tubercular activity. Two-dimensional (2D) and three-dimensional (3D) QSAR studies were performed using multiple linear regression (MLR) analysis and k-nearest neighbour molecular field analysis (kNN-MFA), respectively. The developed QSAR models were found to be statistically significant with respect to training, cross-validation, and external validation. New chemical entities (NCEs) were designed based on the results of the 2D- and 3D-QSAR. NCEs were subjected to Lipinski’s screen to ensure the drug-like pharmacokinetic profile of the designed compounds in order to improve their bioavailability. Also, the binding ability of the NCEs with enoyl-ACP (CoA) reductase was assessed by docking.

Highlights

Tuberculosis caused by Mycobacterium tuberculosis has become a global threat due to the emergence of resistant mycobacterium strains resulting in multiple drug-resistant
Of the different targets being explored in Mycobacteria for antitubercular activity, fatty acid synthesis inhibition is an attractive target for the rational design of new antitubercular agents
The present study was focused on the development of the potential compound containing the pyrrole-ligated oxadiazole analogue with anti-TB activity using quantitative structure-activity relationship (QSAR) studies. 2D- and 3D-QSAR results shed light on the electronic, steric, hydrophobic, and topological nature of the substitution pattern around the selected pyrrole-ligated oxadiazole pharmacophore

Summary

Introduction

Of the different targets being explored in Mycobacteria for antitubercular activity, fatty acid synthesis inhibition is an attractive target for the rational design of new antitubercular agents. The synthesis is catalyzed by FAS-I, whereas in Mycobacterium it is catalyzed by FAS-I and FAS-II This difference renders FAS-II an attractive target for antitubercular discovery. Some of the pyrrole derivatives are known to act as antitubercular by inhibiting the enzyme, FabI involved in fatty acid synthesis in Mycobacterium [4, 12,13]. Computational methods are an important tool in designing newer potent molecules [14] These techniques have been used to study pyrrole derivatives [15, 16]. Docking studies provided insight of the interaction of the compounds with the enzyme

Results and Discussion

Materials and Methods

Conclusion