Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, 0000, Accra, Ghana.
West African Center for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, 0000, Accra, Ghana.
Chem Biodivers. 2022 Sep;19(9):e202200160. doi: 10.1002/cbdv.202200160. Epub 2022 Aug 31.
Mycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS-MODEL, were used in modelling the three-dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co-crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.
分枝杆菌膜蛋白 Large（MmpL）属于抗性、结节和分裂（RND）蛋白超家族，在聚合物、脂质和免疫调节剂的运输中发挥关键作用。MmpL 已成为近年来出现的重要治疗药物靶点之一。在这项研究中，使用了两种同源建模技术，Modeller 和 SWISS-MODEL，使用 M. smegmatis 的结构作为模板，对结核分枝杆菌的 MmpL3 的三维蛋白质结构进行建模。使用分子对接技术筛选了 MmpL3 抑制剂（如 BM212、NITD304、SPIRO 和 NITD349）以及共晶配体 AU1235、ICA38、SQ109 和利莫那班，针对建模结构和 M. smegmatis 的 Mmpl3 进行了筛选。使用分子动力学模拟和分子力学泊松-玻尔兹曼表面面积计算分析了蛋白质-配体相互作用。鉴定了新的残基 Gln32、Leu165、Ile414 和 Phe35 对结合结核分枝杆菌 MmpL3 是关键的，并讨论了抑制剂结合时的构象动力学。
