Design of Novel Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors: Virtual Screening, Synthesis and In Vitro Biological Activities

Abstract

Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis. Here we report new inhibitors active against MTB PS developed using energy based pharmacophore modelling of the available proteininhibitor complex (3IVX) and virtual screening of a large commercial library. The e-pharmacophore model consisted of a ring aromatic (R), negative ionizable (N) and acceptor (A) sites. Compounds 5 and 10 emerged as promising hits with IC50 s 2.18 µM and 6.63 µM respectively. Further structural optimization was attempted to optimize lead 10 using medicinal chemistry approach and six compounds were found to exhibit better enzyme inhibition compared to parent compound lead 10 (<6 µM).

Identification of coumarin derivatives targeting acetylcholinesterase for Alzheimer's disease by field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, MM/GBSA, ADME and MD Simulation study

“…= 400 kDa) obtained from Schrödinger database ( http://www.schrodinger.com/glidedecoyset ) and enrichment calculation was carried out. Enrichment factor (EF) was used to describe number of known inhibitors recovered during screening ( Devi et al, 2015 ). Standard enrichment calculation parameters including EF 1% (enrichment in the top 1% of the decoys), Phase Hypo Score, and BEDROC160.9 score was analyzed to validate the best pharmacophore model.…”

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

“…Pantothenate, also known as vitamin B5, serves as a crucial building block for CoA production, which is primarily involved in the synthesis of mycolic MA 162 . Notably, PanD is conspicuously absent in mammalian systems, thereby indicating the therapeutic potential of PanD inhibitors 163 . PanD, along with pantothenate synthase, has piqued the interest of researchers in the development of PZA, a Group C anti‐TB drug 164 .…”

“… 162 Notably, PanD is conspicuously absent in mammalian systems, thereby indicating the therapeutic potential of PanD inhibitors. 163 PanD, along with pantothenate synthase, has piqued the interest of researchers in the development of PZA, a Group C anti‐TB drug. 164 PZA functions as a prodrug that is enzymatically activated by nicotinamidase or pyrazinamidase (PZAse), encoded by the pncA gene in Mtb , thereby promoting its conversion into the pharmacologically active pyrazinoic acid (POA).…”

Inhibitors of pantothenate synthetase ofMycobacterium tuberculosis– a medicinal chemist perspective

“…emerged as the most active one with IC 50 0.53 AE 0.13 mM against MTB PS and MIC 3.53 mM against MTB H 37 RV strain. Further, this compound exhibited only 10.4% cytotoxicity at 50 mM against mouse macrophage RAW 264.7 cell line 49. …”