Isa Mustafa Alhaji, Abubakar Mustapha B, Mohammed Mohammed Mustapha, Ibrahim Muhammad Musa, Gubio Falmata Audu
Department of Microbiology, Faculty of Sciences, University of Maiduguri, P.M.B. 1069, Maiduguri, Nigeria.
Department of Veterinary Microbiology, Faculty of Veterinary Medicine, University of Maiduguri, Nigeria.
Heliyon. 2021 Nov 29;7(12):e08482. doi: 10.1016/j.heliyon.2021.e08482. eCollection 2021 Dec.
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 (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.
ATP合酶亚基c（AtpE）是一种酶，在来自结核分枝杆菌（MTB）的钠或质子梯度存在的情况下，催化由ADP产生ATP。这种酶被认为是药物设计的一个重要靶点，并且与异烟肼的靶点具有相同的途径。因此，这种酶可作为异烟肼的替代靶点。基于同源建模原理，使用Modeller9.16构建了AtpE的三维（3D）模型结构。使用分子动力学（MD）模拟对开发的模型进行能量最小化和优化。使用RASPD和PyRx工具，将最小化的模型结构与锌和PubChem数据库进行比对，以确定与该酶结合且结合能最小的配体。总共选择了4776种能够以最小结合能与AtpE结合的化合物。对这些化合物进一步筛选其理化性质（Lipinski五规则）。选择了所有具有所需性质的化合物并用于分子对接分析。选择了五种结合能最小在-8.69至-8.44千卡/摩尔之间且小于ATP自由结合能的化合物。对这些化合物进一步筛选其吸收、分布、代谢、排泄和毒性（ADME和毒性）性质。在这五种化合物中，三种（ZINC14732869、ZINC14742188和ZINC12205447）符合所有ADME和毒性性质，并进行了MD模拟和分子力学广义玻恩表面积（MM-GBSA）分析。结果表明，这些配体形成了相对稳定的复合物，且具有小于ATP结合能的自由结合能。因此，在成功的实验验证后，这些配体被认为是结核分枝杆菌的潜在抑制剂。
