title: CoMFA based de novo design of pyrrolidine carboxamides as inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis.
abstract: InhA, the enoyl acyl carrier protein reductase (EACP reductase) from Mycobacterium tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective target for the development of anti-microbial agents. We report here, comparative molecular field analysis (CoMFA) studies and subsequent de novo ligand design using the LeapFrog program on pyrrolidine carboxamides, which have been reported as selective inhibitors of EACP reductase from Mycobacterium tuberculosis. The CoMFA model, constructed from the inhibitors used in this study has been successfully used to rationalize the structure-activity relationship of pyrrolidine carboxamides. The CoMFA model produced statistically significant results with cross-validated and conventional correlation coefficients of 0.626 and 0.953 respectively. Further, the predictive ability of CoMFA model was determined using a test set which gave predictive correlation coefficient r2 (pred) of 0.880, indicating good predictive power. Finally, Leapfrog was used to propose 13 new pyrrolidine carboxamide analogues, based on the information derived from the CoMFA contour maps. The designed molecules showed better predicted activity using the CoMFA model with respect to the already reported systems; hence suggesting that newly proposed molecules in this series of compounds may be more potent and selective toward EACP reductase inhibition.
authors.affiliation: Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow, 226 001, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium