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.
Highlights
L-Aspartate a-alpha decarboxylase (ADC, EC 4.1.1.11), encoded by the panD gene, is a lyase and catalyzes the decarboxylation of aspartate to b-alanine, which is essential for D-pantothenate formation (Fig. S1)
Structural overview of L-asparate a-decarboxylase Gopalan and co-workers have solved the crystal structure of uncleaved Mycobacterium tuberculosis L-aspartate a-decarboxylase (MtbADC) (2C45) at 2.99 Aresolution [13].The structural superimposition of processed MtbADC, Thermus thermophilus ADC (TthADC):fumarate complex and Helicobacter pylori ADC (HpyADC):isoasparagine complex shows that both substrate analogs bind to the active site (Fig. 1a), which is formed at the interface of a dimer in a similar orientation and are surrounded by conserved residues (Fig. 1b)
The binding of the substrate analogs to TthADC and HpyADC does not significantly change the structure of the enzyme which is evident from the root mean square deviation (RMSD) values of 0.19 and 0.13 Afor 95 Ca atom pairs, respectively
Summary
L-Aspartate a-alpha decarboxylase (ADC, EC 4.1.1.11), encoded by the panD gene, is a lyase and catalyzes the decarboxylation of aspartate to b-alanine, which is essential for D-pantothenate formation (Fig. S1). B-alanine and D-pantoate condense to form pantothenate, a precursor of coenzyme A (CoA), which functions as an acyl carrier in fatty acid metabolism and provides the 49-phosphopantetheine prosthetic group in fatty acid biosynthesis, an essential need for the growth of several microorganisms, including Mycobacterium tuberculosis (Mtb) [2,3], the causative bacterial agent of tuberculosis (Tb) [4]. Since pantothenate is synthesized only in microorganisms, fungi and plants, but not in humans, the enzymes that are involved in this biosynthetic pathway qualify to be potential targets for antibacterial and antifungal agents [9]. The absence of this pathway in humans ensures that any inhibitor or drug against ADC would have low toxicity in patients. The presence of the ADC gene in only one copy in the Mtb genome further enhances its importance as a suitable drug target
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