Identification of potent inhibitors of ATP synthase subunit c (AtpE) from Mycobacterium tuberculosis using in silico approach.

ATP synthase subunit c (AtpE) is an enzyme that catalyzes the production of ATP from ADP in the presence of sodium or proton gradient from Mycobacterium tuberculosis (MTB). This enzyme considered an essential target for drug design and shares the same pathway with the target of Isoniazid. Thus, this enzyme would serve as an alternative target of the Isoniazid. The three dimensional (3D) model structure of the AtpE was constructed based on the principle of homology modeling using the Modeller9.16. The developed model was subjected to energy minimization and refinement using molecular dynamic (MD) simulation. The minimized model structure was searched against Zinc and PubChem database to determine ligands that bind to the enzyme with minimum binding energy using RASPD and PyRx tool. A total of 4776 compounds capable of bindings to AtpE with minimum binding energy were selected. These compounds further screened for physicochemical properties (Lipinski rule of five). All the compounds that possessed the desirable property selected and used for molecular docking analysis. Five (5) compounds with minimum binding energies ranged between ─8.69, and ─8.44 kcal/mol, less than the free binding energy of ATP were selected. These compounds further screened for the absorption, distribution, metabolism, excretion, and toxicity (ADME and toxicity) properties. Of the five compounds, three (ZINC14732869, ZINC14742188, and ZINC12205447) fitted all the ADME and toxicity properties and subjected to MD simulation and Molecular Mechanics Generalized Born and Surface Area (MM-GBSA) analyses. The results indicated that the ligands formed relatively stable complexes and had free binding energies, less than the binding energy of the ATP. Therefore, these ligands considered as prospective inhibitors of MTB after successful experimental validation.