Structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with pyrazinamidase from mycobacterium tuberculosis due to mutagenicity
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Date
2018
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Publisher
ournal of Molecular Graphics and Modelling
Abstract
Pyrazinamide is known to be the most effective treatment against tuberculosis disease and is
known to have bacteriostatic action. By targeting the bacterial spores, this drug reduces the
chances for the progression of the infection in organisms. In recent years, increased instances
of the drug resistance of bacterial strains are reported. Pyrazinamidase, activator for
pyrazinamide, leads to resistance against the drug due to mutagenicity across the world. The
present study aimed at the quantum mechanistic analysis of mutations in pyrazinamidase to
gain insights into the mechanism of this enzyme. Quantum mechanical calculations were
performed to analyse the effect of mutations at the metal coordination site using ORCA
software program. Moreover, conformational changes in PZase binding cavity has also been
analysed due to mutations of binding pocket residues using CASTp server. In order to elucidate
the behaviour of the mutant pyrazinamidase, docking of PZA in the binding pocket of PZase
was performed using AutoDock Vina. Analysis of results revealed that iron showed weak
binding with the metal coordination site of the mutant proteins due to alteration in electron
transfer mechanism. The binding cavity of the mutant PZase has undergone major
conformational changes as the volume of pocket increased due to bulky R-chains of mutated
amino acids. These conformational changes lead to weak binding of the drug at binding cavity
of PZase and reduce the drug activation mechanism leading to increased drug resistance in the
bacterial strains.
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Keywords
Mycobacterium tuberculosis; Pyrazinamidase; Pyrazinamide; Mutagenicity; Quantum mechanics; DFT; Molecular docking
Citation
Rasool, N., Iftikhar, S., Amir, A., & Hussain, W. (2018). Structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with pyrazinamidase from Mycobacterium tuberculosis due to mutagenicity. Journal of Molecular Graphics and Modelling, 80, 126-131.