Molecular investigation of active binding site of Isoniazid (INH) and insight into resistance mechanism of S315T-MtKatG in Mycobacterium tuberculosis

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 105; pp. 18 - 27
• Main Authors: Srivastava, Gaurava, Tripathi, Shubhandra, Kumar, Akhil, Sharma, Ashok
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.07.2017; Elsevier Science Ltd
• Subjects: Antitubercular Agents - chemistry; Antitubercular Agents - metabolism; Antitubercular Agents - therapeutic use; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Binding energy; Binding Sites; Catalase - chemistry; Catalase - genetics; Catalase - metabolism; Crystal structure; Drug resistance; Drug Resistance, Multiple, Bacterial - genetics; FEL; Free energy; Genotype; Heme; Humans; Infectious Disease; INH binding site; INH resistance; Isoniazid; Isoniazid - chemistry; Isoniazid - metabolism; Isoniazid - therapeutic use; MDR TB; MM-PBSA; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Multidrug resistant organisms; Mutation; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - pathogenicity; PCA; Phenotype; Principal components analysis; Protein Binding; Protein Conformation; Proteins; Pulmonary/Respiratory; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant - diagnosis; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - microbiology; Mycobacterium tuberculosis KatG; Multi drug resistant; INH; Molecular dynamics; MM-PBSA; FEL; Free energy landscape; INH binding site; TB; PCA; Mycobacterium tuberculosi; Tuberculosis; MD; INH resistance; MDR TB; MDR; Mtb; MtKatG; IBS; Isoniazid; Principal component analysis
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2017.04.002

Abstract Multi drug resistant tuberculosis is a major threat for mankind. Resistance against Isoniazid (INH), targeting MtKatG protein, is one of the most commonly occurring resistances in MDR TB strains. S315T-MtKatG mutation is widely reported for INH resistance. Despite having knowledge about the mechanism of INH, exact binding site of INH to MtKatG is still uncertain and proposed to have three presumable binding sites (site-1, site-2, and site-3). In the current study docking, molecular dynamics simulation, binding free energy estimation, principal component analysis and free energy landscape analysis were performed to get molecular level details of INH binding site on MtKatG, and to probe the effect of S315T mutation on INH binding. Molecular docking and MD analysis suggested site-1 as active binding site of INH, where the effects of S315T mutation were observed on both access tunnel as well as molecular interaction between INH and its neighboring residues. MMPBSA also supported site-1 as potential binding site with lowest binding energy of −44.201 kJ/mol. Moreover, PCA and FEL revealed that S315T mutation not only reduces the dimension of heme access tunnel but also showed that extra methyl group at 315 position altered heme cavity, enforcing heme group distantly from INH, and thus preventing INH activation. The present study not only investigated the active binding site of INH but also provides a new insight about the conformational changes in the binding site of S315T-MtKatG.