Docking Simulations and QM/MM Studies between Isoniazid Prodrug, Catalase-Peroxidase (KatG) and S315T Mutant from Mycobacterium tuberculosis

Isoniazid (INH), an antibiotic used to treat tuberculosis (TB), is a prodrug requiring activation by the Mycobacterium tuberculosis KatG (mtKatG). In the present work, theoretical calculations were carried out to locate the most energetically-favorable INH–KatG interaction modes using the experimental structure of a wild type and mutant mtKatG active site. The S315T mutation significantly affects the ability of the enzyme to convert INH to isonicotinic acid in vitro. The results showed that significant changes occur in the INH binding pattern when serine is replaced by threonine.