Discovery of Mycobacterium tuberculosis α-1,4-glucan branching enzyme (GlgB) inhibitors by structure- and ligand-based virtual screening.

Dkhar, Hedwin Kitdorlang and Gopalsamy, Anupriya and Loharch, Saurabh and Kaur, Amandeep and Bhutani, Isha and Saminathan, Kanmani and Bhagyaraj, Ella and Chandra, Vemika and Swaminathan, Kunchithapadam and Agrawal, Pushpa and Parkesh, Raman and Gupta, Pawan (2015) Discovery of Mycobacterium tuberculosis α-1,4-glucan branching enzyme (GlgB) inhibitors by structure- and ligand-based virtual screening. The Journal of biological chemistry, 290 (1). pp. 76-89. ISSN 1083-351X

PDF Pawan Gupta J. Biol. Chem.-2014-Dkhar-jbc.M114.589200.pdf - Published Version Restricted to Registered users only Download (1356Kb)

Abstract

GlgB (α-1,4-glucan branching enzyme) is the key enzyme involved in the biosynthesis of α-glucan, which plays a significant role in the virulence and pathogenesis of Mycobacterium tuberculosis. Because α-glucans are implicated in the survival of both replicating and non-replicating bacteria, there exists an exigent need for the identification and development of novel inhibitors for targeting enzymes, such as GlgB, involved in this pathway. We have used the existing structural information of M. tuberculosis GlgB for high throughput virtual screening and molecular docking. A diverse database of 330,000 molecules was used for identifying novel and efficacious therapeutic agents for targeting GlgB. We also used three-dimensional shape as well as two-dimensional similarity matrix methods to identify diverse molecular scaffolds that inhibit M. tuberculosis GlgB activity. Virtual hits were generated after structure and ligand-based screening followed by filters based on interaction with human GlgB and in silico pharmacokinetic parameters. These hits were experimentally evaluated and resulted in the discovery of a number of structurally diverse chemical scaffolds that target M. tuberculosis GlgB. Although a number of inhibitors demonstrated in vitro enzyme inhibition, two compounds in particular showed excellent inhibition of in vivo M. tuberculosis survival and its ability to get phagocytosed. This work shows that in silico docking and three-dimensional chemical similarity could be an important therapeutic approach for developing inhibitors to specifically target the M. tuberculosis GlgB enzyme.

Item Type:	Article
Additional Information:	Copyright of this article belongs to ASBMB.
Uncontrolled Keywords:	Docking; Molecular Docking; Mycobacterium tuberculosis; Pathogenesis; Small Molecule
Subjects:	Q Science > QR Microbiology
Depositing User:	Dr. K.P.S.Sengar
Date Deposited:	13 Jul 2015 10:44
Last Modified:	14 Jul 2015 04:34
URI:	http://crdd.osdd.net/open/id/eprint/1650

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