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

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.
AuthorsShalini Saxena, Parthiban Brindha Devi, Vijay Soni, Perumal Yogeeswari, Dharmarajan Sriram
JournalJournal of molecular graphics & modelling (J Mol Graph Model) Vol. 47 Pg. 37-43 (Feb 2014) ISSN: 1873-4243 [Electronic] United States
PMID24316937 (Publication Type: Journal Article)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Ligands
  • Alanine Dehydrogenase
Topics
  • Alanine Dehydrogenase (antagonists & inhibitors, chemistry, metabolism)
  • Binding Sites
  • Catalytic Domain
  • Databases, Factual
  • Drug Design
  • Enzyme Inhibitors (chemistry, metabolism)
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Mycobacterium tuberculosis (chemistry, enzymology)
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship

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