Understanding the Structural Importance of the Non-Binding and Binding Parts of Bedaquiline and Its Analogues With ATP Synthase Subunit C Using Molecular Docking, Molecular Dynamics Simulation and 3D-QSAR Techniques

Posted: 19 Feb 2020

Date Written: February 19, 2020

Abstract

Bedaquiline is a diarylquinoline antimycobacterial drug prescribed 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 the ATP rotor complex, it is necessary to know the importance of the whole moiety that includes the major part of the molecule which does not bind to the receptor. For this purpose, a set of reported diarylquinolines which have been evaluated against Mycobacterium tuberculosis were chosen for this study. Molecular Docking studies were done to identify the essential interactions that were responsible for binding with the protein. This was further validated by the molecular dynamics simulation studies done with few of the active and inactive molecules. Furthermore, Quantitative Structure Activity Relationship (QSAR) studies were done to obtain statistically acceptable Field-based and Atom-based models (Q^2 > 0.7, R^2 > 0.80 and Rcv^2 > 0.6). Their contours were elaborately studied which helped us to distinguish the binding and non-binding structural features of the molecules with the protein. The knowledge about the essential structural requirements were gained by integrating all the computational studies. The structural insight gained from this study would be of help in designing molecules with better antitubercular activity in future.

Keywords: Mycobacterium tuberculosis, QSAR, Molecular Docking, Molecular dynamics, Bedaquiline

Suggested Citation

Ray, Rajdeep, Understanding the Structural Importance of the Non-Binding and Binding Parts of Bedaquiline and Its Analogues With ATP Synthase Subunit C Using Molecular Docking, Molecular Dynamics Simulation and 3D-QSAR Techniques (February 19, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3540793

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