Identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate a-decarboxyalse (ADC)

Abstract

L-Aspartate a-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to ?-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including <i>Mycobacterium tuberculosis </i>(Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. Cleaved <i>Mycobacterium tuberculosis </i> L-Aspartate a-decarboxylase (MtbADC) structure was modelled and based on chemoinformatics drug-design approach, potential drug-like inhibitors against MtbADC were identified, following which we employed proton Nuclear Magnetic Resonance (NMR) based assay to systematically screen the inhibitors that we have earlier identified from the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases and those reported earlier in the literature(Sharma et al., PLoS ONE 7,e33521, 2012). The concentrations of substrate and product in the reaction were quantified with time and the percentage of conversion and a relative inhibition constant ( <i>k_rel </i>) were used to compare the inhibitory properties of the previously known molecules: oxaloacetate, DL-threo-?-hydroxy aspartate, L-glutamate and L-cysteic acid with relative inhibition constant <i>k_rel </i> values of 0, 0.36, 0.40 and 0.40, respectively and the newly identified molecules: D-tartaric acid, L-tartaric acid and 2,4-dihydroxypyrimidine-5-carboxylic acid with <i>k_rel </i>values of 0.36, 0.38 and 0.54, respectively(Sharma et al., PLoS ONE 7(9), e45947, 2012). Novel inhibitors were further tested for their inhibitory activity against Mtb culture. These molecules could serve as potential building blocks for developing better therapeutic agents.