Computer-Aided Drug Design of Potential Anti-Tubercular Drug Targeting the Mycobacterial F-Type ATP Synthase Enzyme

Tuberculosis (TB) remains one of the leading infectious diseases with a significant impact on morbidity and mortality worldwide. Mycobacterium tuberculosis (Mtb), the causative agent of TB, is highly dependent on the electron transport chain (ETC) pathway for the generation of energy. Mycobacteria opportunistically move to another site for energy generation if any of their ETC sites are inhibited by any drug. In this study, we aim to design and evaluate novel scaffolds as potential anti-tubercular agents targeting the inhibition of ATP synthase. Recently, an Amiloride derivative HM2-16F was reported as an anti-tubercular agent targeting the inhibition of Mtb ATP synthase. Using HM2-16F as template compound, a library of the novel compounds was generated and subjected to docking analysis against the mycobacterial F-type ATP synthase (PDB-ID: 4V1F). The designed new compounds were found to have optimal ADMET properties and predicted binding affinity comparable to Bedaquiline. The benzofuran ring of compounds 4, 5, and 11 showed π-π interactions with Phe69, whereas compound 5 formed hydrogen bond with Gly62 (backbone) and with Glu65. Furthermore, compounds 4 and 11 showed hydrogen bond interaction with Glu65. Further synthesis and biological evaluation of the designed compounds may lead to a potential drug candidate against TB.