Pyrazinamidase (PZase) plays a key role in activating the prodrug Pyrazinamide (PZA) - an important drug in the anti tuberculosis therapy. Mutation in pncA gene coding for PZase is a major mechanism of PZA resistance in Mycobacterium tuberculosis. PZase was modeled using software Discovery Studio (DS) 1.7 based on the crystal structure of the PZase from Pyrococcus horikoshii (PDB code 1im5), in this study. The model was assessed by PROCHECK and VERIFY-3D graph. It comprises of one sheet with 6 parallel strands and 7 helices. The amino acids analyzed at the active site were Asp8, Asp49, Trp68, Lys96, Ala134, Thr135 and Cys138. Two mutants were generated with Tyr and Ser at position 138. A flexible docking study with PZA was performed with all the three models and the results indicate that Cys138Tyr substitution may lead to higher degree of drug resistance than Cys138Ser. The study provides details about the structural prediction of PZase from M. tuberculosis. The predicted model will enable us to explore more about the drug-target interaction and giving idea relating to the resistance mechanism, occurring due to mutations at the active site of the target protein.

Key words:M. tuberculosis, PZase, PZA, drug resistance, mutants, docking.