Ultra-large library docking for novel Tuberculosis ATP synthase inhibitors
Mycobacterial infections, such as tuberculosis (TB) infections, pose a significant global health challenge. Mycobacterial ATP synthase has emerged as a promising target for antibiotics to treat these infections. For example, ATP synthase is required for Mtb growth and survival in a non-replicating (NR) state and is a clinically validated TB drug target for drug bedaquiline (BDQ). However, BDQ has two major issues: 1) side effects due to its lipo-philicity and off-target activity against the hERG channel; and 2) emergence of BDQ-resistant strains of Mtb due to drug efflux or rare mutations in ATP synthase. Two recent breakthroughs in this field provide a great opportunity to overcome the limitations mentioned above. Firstly, high-resolution CryoEM structures of ATP synthase bound to BDQ and SQ31f have been determined, providing crucial structural information for rational design of inhibitors and identification of new sites that could potentially overcome BDQ-resistance. Secondly, the innovation of ultra-large library docking bridges billion+ of available small molecules with good drug-like properties to high-resolution structures, facilitating the discovery of novel and diverse chemotypes. In this project, we propose large-scale structure-based docking screens targeting three distinct ligand-binding sites in M. smegmatis ATP synthase to identify novel inhibitors for TB. Hits from the screen will be followed by biochemical and structural characterization for further optimization to obtain lead compounds with improved drug-like properties and re-duced susceptibility to mutations that cause resistance to BDQ. This research will help address the urgent need for new treatments for TB infections.