Identification of active phytochemical from traditional herbal knowledgebase targeting Pantothenate synthetase for anti-tuberculosis therapy

: Increased numbers of reported cases of Mycobacterium tuberculosis (Mtb) resistance to the generally used antibiotics demand to identify novel therapeutic entities for better control of Tuberculosis. Most of the Structure-based Drug Discovery (SBDD) works reported earlier had screened compounds against a single drug target to avoid any off-target binding and related complications. Because of the development of Multi-Drug Resistant and Extensively Drug-Resistant strains of Mtb and looking into the incurable pathologies, targeting the right drug target with a promising ligand data set will result in effective therapeutics. Simultaneously, traditional knowledge-based drugs have earned little success in developing anti-tuberculosis drugs in recent studies. Combining the right-target approach and traditional herbal knowledge base, this in-silico drug discovery study was carried out where 1236 compounds from two plants, traditionally used for TB treatment, Camellia sinensis, Ginkgo biloba along with the antibacterial compounds of DrugBank Database have been screened against Pantothenate synthetase of Mtb, a well-known drug target for anti-TB therapeutics. Through this analytics, Epigallocatechin gallate (EGCG) of Camellia sinensis has been reported through in silico docking studies and subsequent Molecular Dynamics simulation, as a promising anti-TB candidate due to its affinity towards Pantothenate synthetase of Mtb. EGCG was subjected to ADME-Tox studies as well as 3D QSAR analysis for the detection of its drug-like properties for the determination of IC50 value. The EGCG showed the IC50 value at 1404 nM, which is quite promising for a plant-origin compound. The selected ligand, EGCG, due to its promising affinity towards Pantothenate synthetase of Mtb with high drug-like properties, justifies its selection as a potential anti-tuberculosis compound.

The broad amine scope of pantothenate synthetase enables the synthesis of pharmaceutically relevant amides

Pantothenate synthetase from Escherichia coli (PSE. coli) has a broad substrate scope, accepting diverse amines in the amidation of (R)-pantoate, enabling the facile synthesis of pharmaceutically relevant vitamin B5 antimetabolites.

Molecular docking study on quercetin derivatives as inhibitors of PantothenateSynthetase (PanC) of Mycobacterium tuberculosis

The anti-TB drugs currently in the use are insufficient to address these major health challenges. Hence, it is imperative to discover and develop new and efficient drugs against TB. The enzyme pantothenate synthetase (PS or PanC), necessary for the production of pantothenate (vitamin B5), critical components of fatty acid synthesis, when inhibited will in turn affect the cell wall synthesis of bacilli. In the present study, an attempt will be made to find the drug like molecules from quercetin derivatives prepared in silico to find out possible inhibitors of PanCof M. tuberculosis. The 3D structure of PanC was obtained from RCSB database and quercetin from ZINC database. The derivatives of quercetin were prepared and were docked initially with iGEMDOCK docking tool. The final docking was done in AutoDock vina software. The ADMET properties of the selected ligands were done in admetSAR online server tool. The present study revealed that four derivatives of quercetin has excellent binding with Pantothenate Synthetase (PanC) of M. tuberculosis. These derivatives can be taken for in vitro enzymatic assays for its inhibitory property in the search for new anti-TB drugs.

Design, Synthesis and Evaluation of Aryloxybenzylidene Hydrazinyl-Benzoxazoles/Benzothiazoles Analogs as Antimycobacterial Agents

Substituted 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzothiazole/benzoxazoles series were designed through molecular hybridization and synthesized in condensation reaction of hydrazinylbenzothiazole/ benzoxazole with substituted aryloxy benzaldehydes. All the synthesized compounds were assigned structure based on spectral data and were evaluated for antimycobacterial activity. Among both benzothiazole and benzoxazole derivatives, the compounds 8f and 9e were found to show most potent antitubercular activity with MIC value of 0.89 and 0.92 μM which are on a par with those of standard antitubercular drugs. In order to know the binding interactions of all the compounds were docked within the mycobacterial pantothenate synthetase, which showed interactions with Asp88, Arg200, Ser196, Asn199, Met 195 and Lys 160 of pantothenate synthetase.

Inhibitors of pantothenate synthetase of Mycobacterium tuberculosis – a medicinal chemist perspective

Tuberculosis, leads to numerous deaths worldwide. New drug discovery strategies are need of the hour. In the current review, we focused on the discovery of new antitubercular drugs targeting pantothenate synthetase.

Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy

Background: Pantothenate, the fundamental precursor to coenzyme A, is required for optimal growth and virulence of microbial pathogens. It is synthesized by the enzyme-catalyzed condensation of β-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of β-alanine are gaining inquiry as potential antimicrobial chemotherapeutics. Methods: We synthesized and evaluated 35 derivatives of β-alanine, substituted at the α, β, amine, and carboxyl sites, derived from in silico, dynamic molecular modeling to be potential competitive inhibitors of pantothenate synthetase. Employing the Clinical Laboratory Standards M7-A6 broth microdilution method, we tested these for inhibition of growth in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Results: All compounds proved entirely ineffective in all species tested, with no inhibition of growth being observed up to 200 µM/mL. Conclusions: Upon revision of the literature, we conclude that high enzyme selectivity or external salvage mechanisms may render this strategy futile against most bacteria.