Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.30.228726v1?rss=1 Authors: Cloete, R., Shahbaaz, M., Grobbelaar, M., Sampson, S. L., Christoffels, A. Abstract: Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown, in vitro , to be essential for Mycobacterium tuberculosis growth. It is conserved between mycobacterium species, is up-regulated during dormancy, has a known 3D crystal structure and has no known human homologs. A model of Rv2421c in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed and subject to virtual ligand screening against the Prestwick Chemical Library and the ZINC database, which yielded 155 potential hit molecules. 3D-QSAR studies of the 155 drug molecules indicated five compounds with similar inhibitory efficiencies compared to known inhibitors of Rv2421c. Molecular docking validation and molecular dynamics simulation analysis of the top five compounds indicated that the identified inhibitor molecules bind to Rv2421c with comparable efficiency as the substrate DND. Subsequent in vitro testing of the five compounds identified Novobiocin sodium salt with activity against Mycobacterium tuberculosis at 50 M, 25M and weakly at 10M concentrations. Although, Novobiocin salt targets Mycobacterium tuberculosis DNA gyrase B our studies suggest that it has the potential to be repurposed to inhibit Rv2421c. Subsequent in silico structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest promising alternatives for the treatment of Mycobacterium tuberculosis . Copy rights belong to original authors. Visit the link for more info