Exploring the Mechanism and discovery of potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis

Abstract

The rise of antibiotic-resistant Mycobacterium tuberculosis (MTB) has led to a reduction in the availability of effective medications for tuberculosis therapy, resulting in increased morbidity and mortality globally. Tuberculosis primarily affects the lungs but can also spread to the brain and spine. Pyrazinamide (PZA) is considered to be the most potent drug but it also shows resistance due to mutation at the position G97D. However, the Mechanism of PZA drug resistance towards Mtb PZase is unclear. Moreover, due to mutations that provide PZA resistance, there is no such evidence about the structural dynamics of Mtb PZase protein. Here we aimed to perform molecular docking, pharmacophore modeling, virtual Screening, and MD simulation, to explore the Mtb PZase protein resistance mechanism toward the PZA drug due to mutation at the G97D position as well as compare the Wild-type and Mutant-type PZA bound systems. From the analysis, the Wild-type shows good interaction as compared to Mutant-type PZA bound systems. Then we performed pharmacophore-based virtual screening against commercially available databases i.e. ZINC and Chembridge. Finally, we selected a total of 5 lead compounds based on docking score and good interaction. The selected compounds considered has a good ADMET property, because the compound shows no pan Assay interference (PAINS) indicating that these compound could be useful inhibitors of Mutant-type PZA bound systems.