title: Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
abstract: L-aspartate α-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to β-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. We have followed a chemoinformatics-based approach to identify potential drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase (MtbADC). The structure-based high throughput virtual screening (HTVS) mode of the Glide program was used to screen 333,761 molecules of the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases. Ligands were rejected if they cross-reacted with S-adenosylmethionine (SAM) decarboxylase, a human pyruvoyl dependent enzyme. The lead molecules were further analyzed for physicochemical and pharmacokinetic parameters, based on Lipinski's rule of five, and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. This analysis resulted in eight small potential drug-like inhibitors that are in agreement with the binding poses of the crystallographic ADC:fumarate and ADC:isoasparagine complex structures and whose backbone scaffolds seem to be suitable for further experimental studies in therapeutic development against tuberculosis.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Reetu
authors.initials: R
authors.lastname: Sharma
authors.forename: Roopa
authors.initials: R
authors.lastname: Kothapalli
authors.forename: Antonius M J
authors.initials: AM
authors.lastname: Van Dongen
authors.forename: Kunchithapadam
authors.initials: K
authors.lastname: Swaminathan
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D012984:Software
chemical_list: D004791:Enzyme Inhibitors; C019104:aspartate-alpha-decarboxylase; D005968:Glutamate Decarboxylase