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.

A central role for aspartate in Mycobacterium tuberculosis physiology and virulence

“…In addition to serve as a nitrogen provider, aspartate possesses non-redundant and essential functions in bacterial metabolism. As a consequence, several enzymes involved in aspartate metabolism, namely the aspartate decarboxylase PanD, the aspartokinase ASK, and the aspartate-β-semialdehyde dehydrogenase ASD, are considered promising targets for novel antituberculous compounds (Shafiani et al, 2005; Gopalan et al, 2006; Chaitanya et al, 2010; Sharma et al, 2012a,b). PanD is the sole enzyme in M. tuberculosis mediating the decarboxylation of aspartate, which allows the formation of vitamin B5, a precursor of the coenzyme A (CoA) co-factor.…”

Validation of Drug-Like Inhibitors against Mycobacterium Tuberculosis L-Aspartate α-Decarboxylase Using Nuclear Magnetic Resonance (1H NMR)

“…All newly tested compounds were selected upon ensuring both a direct interaction with Arg54 residue, while excluding contact with the MtbADC pyruvoyl group [9]. Our data clearly reveal that the inhibitory potential of the tested ligands is, actually, directly dependent on the number of carboxylate groups present.…”

Synthesis, evaluation, molecular docking, and molecular dynamics studies of novel N‐(4‐[pyridin‐2‐yloxy]benzyl)arylamine derivatives as potential antitubercular agents

“…After 24 hr, any color change from violet to pink was recorded as positive. The lowest concentration where color change occurred was considered as the activity of the compound (Sharma, Kothapalli, Dongen, & Swaminathan, ).…”

“…The drug‐like properties of the synthesized compounds were calculated using the QikProp module (v 5.4, Schrodinger release 2017‐4). The properties such as molecular weight, hydrogen bond donor, hydrogen bond acceptor, log p , QPlog S, QPPCaco, QPlogBB, QPPMDCK, Percent Human Oral Absorption, CNS activity, and QPlogKhsa (Lipinski, Lombardo, Dominy, & Feeney, ; Sharma et al, ; Veber et al, ) were predicted using the QikProp module.…”