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

• Mycobacterium tuberculosisl-alanine dehydrogenase (l-AlaDH) enzyme catalyzes the oxidative deamination of l-alanine to pyruvate.
• Inhibitors for l-AlaDH were designed by structure-based virtual screening of Asinex database using energy-optimized pharmacophore modeling.
• We identified five compounds with IC50 values in the range of 35–80 μM.

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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