title: 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).
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Parthiban Brindha
authors.initials: PB
authors.lastname: Devi
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Jogula
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Asireddy Parameshwar
authors.initials: AP
authors.lastname: Reddy
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Jonnalagadda Padma
authors.initials: JP
authors.lastname: Sridevi
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Centre for Infectious Diseases Research, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Hyderabad-500078, India phone: +9140-66303515; fax: +9140-66303998. pyogee@hyderabad.bits-pilani.ac.in.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D062126:Databases, Chemical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010453:Peptide Synthases; C022318:pantothenate synthetase
keywords: Enzyme ïnhibition; Hit optimisation; Pantothenate synthetase; Tuberculosis; Virtual screening; e-Pharmacophore