Ameeruddin Nusrath Unissa1, George Priya Doss C2, Thirumal Kumar2, Sukumar Swathi3, Appisetty Ramya Lakshmi3, Luke Elizabeth Hanna3. 1. Centre for Biomedical Informatics, National Institute for Research in Tuberculosis, Chennai, India. Electronic address: nusrathunissa@gmail.com. 2. Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. 3. Centre for Biomedical Informatics, National Institute for Research in Tuberculosis, Chennai, India.
Abstract
OBJECTIVES: Isoniazid (INH) resistance is a major contributor to the emergence of multidrug resistance in Mycobacterium tuberculosis (MTB), hampering the success of tuberculosis treatment. This study aimed to identify good leads based on INH derivatives against INH-resistant MTB strains. Mutations at codon 315 in the katG gene encoding catalase-peroxidase (KatG) are the major cause of INH resistance in MTB. The most prevalent substitution is S315T; other substitutions include S315I, S315R, S315N and S315G. METHODS: In this study, all five naturally occurring mutants (S315T, S315I, S315R, S315N and S315G) of KatG were docked and simulated with 50 INH derivatives in comparison with the wild-type (WT) KatG. RESULTS: The docking results suggested that compounds C30, C45 and C50 gave the highest scores when bound to the mutants of KatG. Of note, C50 produced a high score with the WT as well as with three mutants (S315T, S315I and S315R). Simulation studies indicated that C50 exhibited minimal deviation and fluctuation between WT and three mutants compared with C30 and C45, which displayed significant changes with WT and the S315N and S315G mutants, respectively. CONCLUSIONS: C50 can be considered as a better lead for INH-resistant strains. These models demonstrate the binding interaction of all naturally occurring KatG mutants of MTB at position 315 with derivatives of INH. This information will be helpful for lead compound-based identification of derivatives that may be used against INH-resistant MTB strains and may provide a useful structural framework for designing new antitubercular agents that can circumvent INH resistance.
OBJECTIVES:Isoniazid (INH) resistance is a major contributor to the emergence of multidrug resistance in Mycobacterium tuberculosis (MTB), hampering the success of tuberculosis treatment. This study aimed to identify good leads based on INH derivatives against INH-resistant MTB strains. Mutations at codon 315 in the katG gene encoding catalase-peroxidase (KatG) are the major cause of INH resistance in MTB. The most prevalent substitution is S315T; other substitutions include S315I, S315R, S315N and S315G. METHODS: In this study, all five naturally occurring mutants (S315T, S315I, S315R, S315N and S315G) of KatG were docked and simulated with 50 INH derivatives in comparison with the wild-type (WT) KatG. RESULTS: The docking results suggested that compounds C30, C45 and C50 gave the highest scores when bound to the mutants of KatG. Of note, C50 produced a high score with the WT as well as with three mutants (S315T, S315I and S315R). Simulation studies indicated that C50 exhibited minimal deviation and fluctuation between WT and three mutants compared with C30 and C45, which displayed significant changes with WT and the S315N and S315G mutants, respectively. CONCLUSIONS: C50 can be considered as a better lead for INH-resistant strains. These models demonstrate the binding interaction of all naturally occurring KatG mutants of MTB at position 315 with derivatives of INH. This information will be helpful for lead compound-based identification of derivatives that may be used against INH-resistant MTB strains and may provide a useful structural framework for designing new antitubercular agents that can circumvent INH resistance.
Authors: D Thirumal Kumar; L Jerushah Emerald; C George Priya Doss; P Sneha; R Siva; W Charles Emmanuel Jebaraj; Hatem Zayed Journal: Metab Brain Dis Date: 2018-07-09 Impact factor: 3.655