Integrated Computational Study for the Identification of Potential Mycobacterial ATP Synthase Inhibitors for Tuberculosis Therapy

Tuberculosis is one of the world’s most infectious killers, and the rate at which resistance to available medication develops is alarming. Targeting the ATP synthase of Mycobacterium tuberculosis as a strategy to kill the bacteria therapeutically has gained traction. Currently, bedaquiline is used as the cornerstone to treat TB; however, the emergence of resistance to this drug has been reported. This underscores the need to develop novel therapeutic agents. In this study, we employed computational techniques through molecular docking, MMPBSA ranking, DFT, and molecular dynamics simulation to screen phytochemicals from Indian medicinal plants for potential ATP synthase inhibitors. Isoverticine and convallamarogenin were identified based on their good docking scores and total free binding energies (-29.27 Kcal/mol and − 28.37 Kcal/mol, respectively). These compounds were shown to possess good reactivity features from DFT studies. They exhibited similar interaction patterns to bedaquiline, characterized by uniquely strong hydrogen and salt bridge interactions with GLU65 of the subunit C in the Fo region. They also exhibited good druglikeness with minimal interference with metabolic enzymes and possessed good toxicity profiles. Molecular dynamics showed the compounds stabilized within the binding site with resultant reduction in the residual fluctuations of the subunit C. In conclusion, isoverticine and convallamarogenin could serve as lead compounds in the development of anti-TB agents.