Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations of Mycobacterium tuberculosis pyrazinamidase.

ABSTRACT: Pyrazinamide (PZA) is the only first-line antitubercular drug active against latent Mycobacterium tuberculosis (Mtb). It is activated to pyrazinoic acid by the pncA-encoded pyrazinamidase enzyme (PZase). Despite the emergence of PZA drug resistance, the underlying mechanisms of resistance remain unclear. This study investigated part of these mechanisms by modelling a PZA-bound wild type and 82 mutant PZase structures before applying molecular dynamics (MD) with an accurate Fe²⁺ cofactor coordination geometry. After observing nanosecond-scale PZA unbinding from several PZase mutants, an algorithm was developed to systematically detect ligand release via centre of mass distances (COM) and ligand average speed calculations, before applying the statistically gui

SUBMITTER: Sheik Amamuddy O 

PROVIDER: S-EPMC7251373 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature