Computational approach to understanding the mechanism of action of isoniazid, an anti-TB drug

International Journal of Mycobacteriology
Lingaraja JenaBhaskar C Harinath

Abstract

Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (MTB), which remains a major cause for morbidity and mortality in several developing countries. Most drug-resistant MTB clinical strains are resistant to isoniazid (INH), a first-line anti-TB drug. Mutation in KatG, a catalase-peroxidase, of MTB is reported to be a major cause of INH resistance. Normally upon activation by KatG, INH is converted to an active intermediate which has antimycobacterial action in MTB. This INH intermediate in the presence of NADH forms INH-NAD adduct which inhibits inhA (2-trans-enoyl-acyl carrier protein reductase) of MTB, thus blocking the synthesis of mycolic acid, a major lipid of the mycobacterial cell wall. In this docking study, the high binding affinity of INH-NAD adduct towards InhA was observed in comparison with INH alone. In this study, two resistant mutants of KatG (S315T and S315N) were modeled using Modeller9v10 and docking analysis with INH was performed using AutoDock4.2 and the docking results of these mutants were compared with the wild type KatG. Docking results revealed the formation of a single hydrogen (H) bond between the secondary amine nitrogen (-NH) of INH with Thr or Asn residues in place of Seri...Continue Reading

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Citations

Mar 12, 2016·International Journal of Mycobacteriology·Lingaraja Jena, Bhaskar C Harinath
Dec 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tomáš GoněcAidan Coffey
Aug 20, 2016·Chemical Biology & Drug Design·Iti SaraavSadhna Sharma
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