title: Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
abstract: The catalytic activity of L-aspartate α-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation of our recent chemoinformatics-based design approach for identifying potential drug-like inhibitors against MtbADC. We report an NMR-based protocol that allows label-free and direct monitoring of enzymatic conversion, which we have combined with a systematic testing of reported and newly identified potential inhibitors against MtbADC. Quantification of enzymatic conversion in the absence and presence of inhibitors allowed for a relative measure of the inhibitory effect (k(rel)). Among the newly identified compounds, D-tartrate, L-tartrate, and 2,4-dihydroxypyrimidine-5-carboxylate were found to inhibit the enzyme with k(rel) values of 0.36, 0.38, and 0.54, respectively. In addition to the identification of potential building blocks for the development of therapeutic agents, the current study highlights the importance of electrostatic interactions governing enzyme-inhibitor binding.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Reetu
authors.initials: R
authors.lastname: Sharma
authors.forename: Mara
authors.initials: M
authors.lastname: Florea
authors.forename: Werner M
authors.initials: WM
authors.lastname: Nau
authors.forename: Kunchithapadam
authors.initials: K
authors.lastname: Swaminathan
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; C019104:aspartate-alpha-decarboxylase; D005968:Glutamate Decarboxylase