College of Pharmacy, Knowledge University, Erbil, Iraq.
College of Pharmacy, Ninevah University, Mosul, Iraq.
J Mol Model. 2023 Aug 16;29(9):281. doi: 10.1007/s00894-023-05650-0.
Modulation of disease progression is frequently started by identifying biochemical pathway catalyzed by biomolecule that is prone to inhibition by small molecular weight ligands. Such ligands (leads) can be obtained from natural resources or synthetic libraries. However, de novo design based on fragments assembly and optimization is showing increasing success. Plasmodium falciparum parasite depends on glutathione-S-transferase (PfGST) in buffering oxidative heme as an approach to resist some antimalarials. Therefore, PfGST is considered an attractive target for drug development. In this research, fragment-based approaches were used to design molecules that can fit to glutathione (GSH) binding site (G-site) of PfGST.
The involved approaches build molecules from fragments that are either isosteric to GSH sub-moieties (ligand-based) or successfully docked to GSH binding sub-pockets (structure-based). Compared to reference GST inhibitor of S-hexyl GSH, ligands with improved rigidity, synthetic accessibility, and affinity to receptor were successfully designed. The method involves joining fragments to create ligands. The ligands were then explored using molecular docking, Cartesian coordinate's optimization, and simplified free energy determination as well as MD simulation and MMPBSA calculations. Several tools were used which include OPENEYE toolkit, Open Babel, Autodock Vina, Gromacs, and SwissParam server, and molecular mechanics force field of MMFF94 for optimization and CHARMM27 for MD simulation. In addition, in-house scripts written in Matlab were used to control fragments connection and automation of the tools.
通过识别易于被小分子配体抑制的生物分子催化的生化途径，通常可以开始调节疾病进展。这些配体（先导化合物）可以从自然资源或合成文库中获得。然而，基于片段组装和优化的从头设计正在显示出越来越多的成功。疟原虫寄生虫依赖谷胱甘肽-S-转移酶（PfGST）来缓冲氧化血红素，作为抵抗一些抗疟药物的一种方法。因此，PfGST 被认为是药物开发的一个有吸引力的靶点。在这项研究中，基于片段的方法被用于设计可以适应 PfGST 谷胱甘肽（GSH）结合位点（G 位点）的分子。
所涉及的方法从与 GSH 亚基（基于配体）等排或成功对接 GSH 结合亚袋（基于结构）的片段构建分子。与 S-己基 GSH 的参考 GST 抑制剂相比，成功设计了具有改善的刚性、合成可及性和与受体亲和力的配体。该方法涉及连接片段以创建配体。然后使用分子对接、笛卡尔坐标优化、简化自由能确定以及 MD 模拟和 MMPBSA 计算来探索这些配体。使用了几个工具，包括 OPENEYE 工具包、Open Babel、Autodock Vina、Gromacs 和 SwissParam 服务器，以及 MMFF94 用于优化和 CHARMM27 用于 MD 模拟的分子力学力场。此外，还使用了在 Matlab 中编写的内部脚本来控制片段连接和工具的自动化。
