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J Mol Graph Model. 2014 Feb;47:37-43. doi: 10.1016/j.jmgm.2013.08.005. Epub 2013 Sep 18.

Identification of novel inhibitors against Mycobacterium tuberculosis L-alanine dehydrogenase (MTB-AlaDH) through structure-based virtual screening.

Author information

1
Computer Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
2
Computer Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
3
Computer Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.

Abstract

Mycobacterium tuberculosis (MTB) the etiological agent of tuberculosis (TB) survives in the human host for decades evading the immune system in a latent or persistent state. The Rv2780 (ald) gene that codes for L-alanine dehydrogenase (L-AlaDH) enzyme catalyzes reversible oxidative deamination of L-alanine to pyruvate and is overexpressed under hypoxic and nutrient starvation conditions in MTB. At present, as there is no suitable drug available to treat dormant tuberculosis; it is essential to identify drug candidates that could potentially treat dormant TB. Availability of crystal structure of MTB L-AlaDH bound with co-factor NAD+ facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. The resulting pharmacophore consisted of three hydrogen bond donor sites (D) and two hydrogen bond acceptor sites (A). The database compounds with a fitness score more than 1.0 were further subjected to Glide high-throughput virtual screening and docking. Thus, we report the identification of best five hits based on structure-based design and their in vitro enzymatic inhibition studies revealed IC₅₀ values in the range of 35-80 μM.

KEYWORDS:

Docking; Glide; Mycobacterium tuberculosis; Pharmacophore; l-Alanine dehydrogenase

PMID:
24316937
DOI:
10.1016/j.jmgm.2013.08.005
[Indexed for MEDLINE]

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