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Design of Novel Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors: Virtual Screening, Synthesis and In Vitro Biological Activities
Author(s) -
Devi Parthiban Brindha,
Jogula Sridhar,
Reddy Asireddy Parameshwar,
Saxena Shalini,
Sridevi Jonnalagadda Padma,
Sriram Dharmarajan,
Yogeeswari Perumal
Publication year - 2015
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201400120
Subject(s) - pharmacophore , virtual screening , mycobacterium tuberculosis , enzyme , chemistry , in vitro , combinatorial chemistry , stereochemistry , biochemistry , tuberculosis , lead compound , computational biology , ring (chemistry) , active site , biology , medicine , organic chemistry , pathology
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 proteininhibitor 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 IC 50 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).