Publication Date:
2017-10-06
Description:
Mycobacterium tuberculosis (Mtb) resistance towards anti-tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi-dormant bacilli when converted into its activated form i.e. pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pnc A gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pnc A mutations. Structural changes caused by mutations were studied with respect to their effects on functionality of protein. Docking was performed to analyze the protein-drug binding and comparative analysis was done to observe how the mutations affect drug binding affinity and binding site on protein. Native PZase protein was observed to have the maximum binding affinity in terms of docking score as well as shape complementarity in comparison to the mutant forms. Molecular dynamics simulation analyses showed that mutation in the 68 th residue of protein results in a structural change at its active site which further affects the biological function of protein i.e. conversion of PZA to POA. Mutations in the protein thereby led to PZA resistance in the bacterium due to the inefficient binding. This article is protected by copyright. All rights reserved
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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