{'fraction_non_alphanumeric': 0.01749271137026239, 'fraction_numerical': 0.0011661807580174927, 'mean_word_length': 5.150537634408602, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Elucidating Isoniazid Resistance Using Molecular Modeling

The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on new drug candidates and the mechanism of drug resistance. Molecular docking and molecular dynamics simulation (MD) were performed to study the binding of isoniazid onto the active site of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) in an attempt to address the mycobacterial resistance against isoniazid. Results show that isonicotinic acyl-NADH (INADH) has an extremely high binding affinity toward the wild type InhA by forming stronger interactions compared to the parent drug (isoniazid) (INH). Due to the increase of hydrophobicity and reduction in the side chain's volume of A94 of mutant type InhA, both INADH and the mutated protein become more mobile. Due to this reason, the molecular interactions of INADH with mutant type are weaker than that observed with the wild type. However, the reduced interaction caused by the fluctuation of INADH and the mutant protein only inflected minor resistance in the mutant strain as inferred from free energy calculation. MD results also showed there exists a water-mediated hydrogen bond between INADH and InhA. However, the bridged water molecule is only present in the INADH-wild type complex, reflecting the putative role of the water molecule in the binding of INADH to the wild type protein. The results support the assumption that the conversion of prodrug isoniazid into its active form INADH is mediated by KatG as a necessary step prior to target binding on InhA. Our findings also contribute to a better understanding of INH resistance in mutant type.