"Identification of alkaloid compounds as potent inhibitors of Mycobacterium tuberculosis NadD using computational strategies"

Abstract

Mycobacterium tuberculosis is leading cause of death worldwide. NAD participates in a host of redox reactions in energy landscape of organisms. Several studies implicate surrogate energy pathways involving NAD pools as important in survival of active as well as dormant mycobacteria. One of the NAD metabolic pathway enzyme, nicotinate mononucleotide adenylyltransferase (NadD) is indispensable in mycobacterial NAD metabolism and is perceived as an attractive drug target in pathogen. In this study, we have employed in silico screening, simulation and MM-PBSA strategies to identify potentially important alkaloid compounds against mycobacterial NadD for structure-based inhibitor development. We have performed an exhaustive structure-based virtual screening of an alkaloid library, ADMET, DFT profiling followed by Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation to identify 10 compounds which exhibit favourable drug like properties and interactions. Interaction energies of these 10 alkaloid molecules range between -190 kJ/mol and -250 kJ/mol. These compounds could be promising starting point in the development of selective inhibitors against Mycobacterium tuberculosis.

Keywords: Alkaloid compounds; Computer-aided drug design; Mycobacteria; NAD metabolism; NadD enzyme; Pharmacophore.