Elucidating pyrazinamide resistance in Mycobacterium tuberculosis by molecular docking.

Pyrazinamide (PZA) - an important drug in the anti-tuberculosis therapy, activated by an enzyme Pyrazinamidase (PZase). The basis of PZA resistance in Mycobacterium tuberculosis (Mtb) is owing to mutation in pncA gene coding for PZase. The identification of the structural or functional defects in the mutant enzymes leading to resistance still remains an area to be explored. The Wild-type (WT) and five mutant models Asp8Gly, Lys96Thr, Ser104Arg, Cys138Ser and Cys138Tyr were docked with PZA and its derivatives. In the present study, docking results has aided in predicting the best form of PZA to bind with mutants of PZase to be compounds-10 and 4. These models represent the first in-silico evidence for the binding interaction of PZase with PZA derivatives/analogues. The models may provide useful chemical insights for designing new anti-TB agents in order to overcome the resistance developed with PZA