分子动力学模拟法研究糖类衍生物与钠-葡萄糖协同转运蛋白2的相互作用

Interaction of carbohydrate derivatives and sodium-glucose cotransporters 2 by molecular dynamic simulation

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 investigate the interactions between carbohydrate derivatives and sodium-glucose cotransporters 2 （SGLT2） using molecular dynamic （MD） method and to explore the mechanisms and structure-activity relationship of SGLT2 inhibitors. Methods The homologous structure of SGLT2 was modeled, the GROMACS program was used to model eight structures, such as SGLT2, SGLT2-glucose compound, and SGLT2-carbohydrate compound. And the root mean square fluctuation （RMSF） of the key residues and ligands and the interaction energy between the ligands and SGLT2 was investigated by trajectory analysis. Results The interaction energy calculated by MD method had the higher correlation with experimental results than that by molecular docking method. HS0, K154, D158, and Y290 were the key residues involved in the interaction, N75 and F453 were the important residues, and W291, Q295, and $393 might be the auxiliary residues. The ligands had a relatively consistent conformation, and fragments A and C played the more important roles in receptor binding. And the size, rigidity, and polarity increasing could elevate the bonding strength. Conclusion MD simulation results could display the good performance of the interaction between the ligands and SGLT2, and could give clear guidance for the design of new SGLT2 inhibitors.