Gaining deeper insights into the surface binding of bedaquiline analogues with the ATP synthase subunit C of: Mycobacterium tuberculosis using molecular docking, molecular dynamics simulation and 3D-QSAR techniques

Bedaquiline is a diarylquinoline antimycobacterial drug prescribed for the treatment of Multidrug-Resistant Tuberculosis (MDR-TB). It targets the energy metabolism of the bacteria by inhibiting the proton pump of mycobacterial ATP synthase subunit C. Since bedaquiline binds to the surface of ATP synthase, it is necessary to know the importance of the whole moiety, which includes the major part of the molecule that does not bind to the receptor. For this purpose, a set of reported bedaquiline analogues acting against Mycobacterium tuberculosis were chosen. Molecular docking studies helped us to identify the essential interactions responsible for the binding with the protein. This was further validated using the molecular dynamics simulation studies performed with few active and inactive molecules. Furthermore, a 3D Quantitative Structure Activity Relationship (3D-QSAR) study was done to obtain a statistically acceptable atom-based model (Q2 > 0.7, R2 > 0.80 and Rcv2 > 0.6). The contours generated from the QSAR study were then utilised to understand the importance of the non-binding part of the molecules. Thus, the integration of different computational studies helped us to gain holistic knowledge about the molecules and the role of their structures in binding with ATP synthase.