<p>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 <i>Mycobacterium tuberculosis</i> (MTB). This enzyme considered an
essential target for drug design and its shares the same pathway with the
target of Isoniazid. Thus, this enzyme would serve as an alternative target of
the Isoniazid. The 3D model structure of the AtpE was constructed based on the
principle of the homology modeling using the Modeller9.16. The developed model
was subjected to the 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
binding to AtpE with minimum binding energies were selected. These compounds
further screened for physicochemical properties (Lipinski rule of five). All
the compounds that possessed the desirable properties selected and used for
molecular docking analysis. Five (5) compounds with minimum binding energies
ranged between ─8.69, and ─8.44kcal/mol, less than the free binding energy of
ATP were selected. These compound 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</p>
Identification of Potent Inhibitors of ATP synthase subunit c (AtpE) from Mycobacterium tuberculosis using in silico Approach
