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目的利用分子动力学模拟方法研究糖类衍生物与钠-葡萄糖协同转运蛋白2(SGLT2)相互作用过程,探索SGLT2抑制剂的微观作用机制和构效关系。方法同源模建SGLT2的结构,利用GROMACS程序包进行SGLT2、SGLT2和葡萄糖复合物、SGLT2与糖类衍生物的复合物等8个结构的模拟计算,通过轨迹分析配体与SGLT2之间及分解结构的相互作用能,考察关键残基和配体的均方根涨落(RMSF)。结果分子动力学模拟得到的配体与受体的相互作用能比对接得分有更高的实验结果相关性和筛选能力。SGLT2参与相互作用的关键残基为H80、K154、D158、Y290,较重要的残基可能为N75和F453,辅助性残基可能为W291、Q295和S393。配体之间具有比较一致的构象,片段A和C对受体结合具有更重要的作用。A片段构象固定,C片段的体积、刚性和极性增加可以增加结合强度。结论分子动力学模拟结果能够较好地表现配体与SGLT2之间的相互作用,对于设计SGLT2抑制剂类新药具有较明确的指导作用。
Objective To study the interaction between saccharide derivatives and sodium-glucose cotransporter 2 (SGLT2) by molecular dynamics simulation and to explore the mechanism of action and structure-activity relationship of SGLT2 inhibitors. Methods The structure of SGLT2 was homologously modeled, and the structures of SGLT2, SGLT2 and glucose complexes, complex of SGLT2 and carbohydrate derivatives were simulated by using GROMACS package. The structures of SGLT2 and SGLT2 Structure interaction energy, examine the root-mean-square root-mean-square (RMSF) of the key residues and ligands. Results The interaction between ligand and receptor obtained by molecular dynamics simulation can have higher correlation and screening ability than docking results. The key residues involved in the interaction of SGLT2 are H80, K154, D158 and Y290. The more important residues may be N75 and F453. The auxiliary residues may be W291, Q295 and S393. Ligands have a more consistent conformation, and fragments A and C play a more important role in receptor binding. Conformational immobilization of A fragments, increase in C-segment volume, rigidity and polarity can increase the binding strength. Conclusions The results of molecular dynamics simulation can well reflect the interaction between ligand and SGLT2 and have a clear guidance for the design of SGLT2 inhibitors.