Molecular Modelling of Novel Selective Inhibitors of Mycobacterium tuberculosis CYP125A1 Protein Based on Natural Product-like Structures

Abstract

Background: Tuberculosis (TB) is the second leading cause of death from infectious diseases, with 10.6 million cases and 1.3 million deaths. Conventional treatment faces difficulties due to the emergence of resistant strains, such as MDR and XDR-TB. M. tuberculosis uses host cholesterol as an energy source, via the CYP125A1 protein, which catalyses cholesterol oxidation, a process critical for the survival of the bacterium. Methods: This study used computational methods to identify selective inhibitors of the CYP125A1 enzyme. A total of 5968 structure-like compounds from the ASINEX database were evaluated for protein-binding affinity. In addition, docking tests were performed to verify whether the identified compounds could interact with other M. tuberculosis proteins, such as InhA and the human CYP3A4 protein to assess possible off-target effects. Results: The top ten compounds showed a good pharmacological profile and favourable binding energies. Compounds LAS 52160899 and LAS 7298627 served as a basis to search for others with known biological activity, with DB07463 and DB01081 selected as candidates. Conclusions: Potential new inhibitors of the CYP125A1 enzyme were identified. These findings highlight the importance of further research to develop new treatments against M. tuberculosis, especially to combat resistant strains.