The outer membrane protein A (OmpATb) of Mycobacterium tuberculosis is a virulence factor that neutralizes the host pH to impede the uptake of hydrophilic antitubercular drugs. Identifying natural compounds with the potential to inhibit OmpATb could allow circumvention of the porin-like activities of OmpATb. Four potential leads comprising ZINC000003958185, ZINC000000157405, ZINC000000001392 and ZINC000034268676 were obtained by virtual screening of 6394 diverse natural products. Characterization of the binding interactions of the potential leads with OmpATb revealed nine critical residues comprising ARG86, LEU110, LEU113, LEU114, ALA115, PHE142, SER145, VAL146, and PHE151. Molecular dynamics simulations also revealed very stable protein-lead complexes. Most residues contributed lower binding energies to the overall molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energies of the interactions between the molecules and OmpATb protein. Induced Fit Docking (IFD) of the compounds regenerated poses of the molecular docking using AutoDock Vina. These molecules could be starting templates for designing inhibitors to bypass the pore mediating activities of OmpATb. Based on structural similarity, ZINC000034268676 was suggested as a potential scaffold for designing efflux pump inhibitors of the gate mediating activities of OmpATb and may enhance the uptake of hydrophilic drugs to reduce the duration time of tuberculosis treatment. Furthermore, structurally similar compounds available in the DrugBank database with a similarity threshold of 0.7 have been reported to exhibit antitubercular and anti-mycobacterial activities. These biomolecules can be further characterized experimentally to corroborate their antitubercular activity. Also, the skeletons of the molecules can be adopted as sub-structures for the design of future anti-mycobacterial drugs.

结核分枝杆菌的外膜蛋白A（OmpATb）是中和宿主pH以阻止亲水性抗结核药物摄取的毒力因子。鉴定具有抑制OmpATb潜能的天然化合物可以规避OmpATb的孔蛋白样活性。通过对6394种不同的天然产物进行虚拟筛选，获得了包括ZINC000003958185，ZINC000000157405，ZINC000000001392和ZINC000034268676在内的四个潜在线索。潜在的潜在客户与OmpATb的结合相互作用的表征揭示了九个关键残基，包括ARG86，LEU110，LEU113，LEU114，ALA115，PHE142，SER145，VAL146和PHE151。分子动力学模拟还显示出非常稳定的蛋白质-铅配合物。大多数残基对整体分子力学泊松-玻尔兹曼表面积（MM-PBSA）结合分子与OmpATb蛋白之间相互作用的自由能贡献了较低的结合能。使用AutoDock Vina，化合物的诱导拟合对接（IFD）可以重新生成分子对接的姿势。这些分子可能是设计抑制剂绕过OmpATb的孔介导活性的起始模板。基于结构相似性，ZINC000034268676被认为是设计OmpATb的门介导活性外排泵抑制剂的潜在支架，并可能增加亲水性药物的吸收以减少结核病治疗的持续时间。此外，在DrugBank数据库中可获得结构相似的化合物，相似性阈值为0。据报道有7种具有抗结核和抗分枝杆菌的活性。这些生物分子可以通过实验进一步表征，以证实其抗结核活性。而且，分子的骨架可以用作未来抗分枝杆菌药物设计的子结构。