Original Paper

Journal of Molecular Modeling

, Volume 17, Issue 4, pp 869-877

First online:

Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: An in silico analysis

  • Rituraj PurohitAffiliated withSchool of Bio Sciences and Technology (SBST), Bioinformatics Division, Vellore Institute of Technology University
  • , Vidya RajendranAffiliated withSchool of Bio Sciences and Technology (SBST), Bioinformatics Division, Vellore Institute of Technology University
  • , Rao SethumadhavanAffiliated withSchool of Bio Sciences and Technology (SBST), Bioinformatics Division, Vellore Institute of Technology University Email author 

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Abstract

Remarkable advances have been made in the drug therapy of tuberculosis. However much remains to be learned about the molecular and structural basis of drug resistance in Mycobacterium tuberculosis. It is known that, activation of Isoniazid (INH) is mediated by Mycobacterium tuberculosis catalase-peroxidase (MtBKatG) and mutation at position 315 (serine to threonine) leads to resistance. We have conducted studies on the drug resistance through docking and binding analysis supported by time-scale (∼1000 ps) and unrestrained all-atom molecular dynamics simulations of wild and mutant MtBKatG. The study showed conformational changes of binding residues. Mutant (S315T) showed high docking score and INH binding affinity as compared to wild enzyme. In molecular dynamics simulation, mutant enzyme exhibited less structure fluctuation at INH binding residues and more degree of fluctuation at C-terminal domain compared to wild enzyme. Our computational studies and data endorse that MtBKatG mutation (S315T) decrease the flexibility of binding residues and made them rigid by altering the conformational changes, in turn it hampers the INH activity. We ascertain from this work that, this study on structural mechanism of resistance development in Mycobacterium tuberculosis would lead to new therapeutics based on the result obtained in this study.

Keywords

Binding affinity Catalase-peroxidase Docking Isoniazid Molecular dynamic simulation Resistance mutation Solvent accessibility