Identification of novel inhibitors against Mycobacterium tuberculosis l-alanine dehydrogenase (MTB-AlaDH) through structure-based virtual screening |
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Affiliation: | 1. Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, PR China;2. Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, PR China |
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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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Keywords: | Pharmacophore Glide Docking |
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