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.
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Authors | Shalini Saxena, Parthiban Brindha Devi, Vijay Soni, Perumal Yogeeswari, Dharmarajan Sriram |
Journal | Journal of molecular graphics & modelling
(J Mol Graph Model)
Vol. 47
Pg. 37-43
(Feb 2014)
ISSN: 1873-4243 [Electronic] United States |
PMID | 24316937
(Publication Type: Journal Article)
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Copyright | Copyright © 2013 Elsevier Inc. All rights reserved. |
Chemical References |
- Enzyme Inhibitors
- Ligands
- Alanine Dehydrogenase
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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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