TY  - JOUR
N1  - Copyright of this article belongs to ASBMB.
ID  - open1650
UR  - http://www.jbc.org/content/290/1/76.long
IS  - 1
A1  - Dkhar, Hedwin Kitdorlang
A1  - Gopalsamy, Anupriya
A1  - Loharch, Saurabh
A1  - Kaur, Amandeep
A1  - Bhutani, Isha
A1  - Saminathan, Kanmani
A1  - Bhagyaraj, Ella
A1  - Chandra, Vemika
A1  - Swaminathan, Kunchithapadam
A1  - Agrawal, Pushpa
A1  - Parkesh, Raman
A1  - Gupta, Pawan
Y1  - 2015/01/02/
N2  - GlgB (?-1,4-glucan branching enzyme) is the key enzyme involved in the biosynthesis of ?-glucan, which plays a significant role in the virulence and pathogenesis of Mycobacterium tuberculosis. Because ?-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.
PB  - ASBMB
JF  - The Journal of biological chemistry
VL  - 290
KW  - Docking; Molecular Docking; Mycobacterium tuberculosis; Pathogenesis; Small Molecule
SN  - 1083-351X
TI  - Discovery of Mycobacterium tuberculosis ?-1,4-glucan branching enzyme (GlgB) inhibitors by structure- and ligand-based virtual screening.
SP  - 76
EP  - 89
ER  -