Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: An in silico analysis |
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Authors: | Purohit Rituraj Rajendran Vidya Sethumadhavan Rao |
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Institution: | (1) School of Bio Sciences and Technology (SBST), Bioinformatics Division, Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India; |
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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. |
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