葡萄糖苷酶抑制剂作用机理的分子动力学模拟和自由能计算

含有锍离子的葡萄糖苷酶抑制剂如kotalanol (SK)和它除去磺酸基团后的衍生物(DSK), 是潜在的毒副作用较小的治疗II 型糖尿病的候选药物. α-葡萄糖苷酶抑制活性实验显示, DSK活性比SK略高, 而将二者环上的S原子替换成NH后(分别称为DSN和SN), DSN的活性要比SN高1500倍左右. 本文用分子动力学模拟, 结合自由能计算和自由能分解的方法对上述四个抑制剂的作用机理进行了研究. 研究结果表明活性的巨大差异是由NH基团取代效应和磺酸基团立体效应共同作用的结果, 由于N―C键长比S―C键长短, NH基团取代导致烷基链的翻转, 同时, 磺酸基团限制了链的翻转, 因此改变了抑制剂的结合模式. 计算结果与实验基本一致.本文的研究结果有助于进一步理解含锍离子的葡萄糖苷酶抑制剂的结合机理, 并为设计更有潜力的葡萄糖苷酶抑制剂提供了有价值的信息.

Interaction Mechanisms of Inhibitors of Glucoamylase by Molecular Dynamics Simulations and Free Energy Calculations

Sulfonium ion glucosidase inhibitors such as kotalanol (SK) and de-O-sulfonated kotalanol (DSK) are potential drug candidates for the treatment of type II diabetes, with no serious toxicity or side effects. Experimental binding assays against glucosidase show that the activity of DSK is slightly higher than that of SK, while the activity of the nitrogen analogue of de-O-sulfonated kotalanol (DSN) is ~1500-fold higher than that of the nitrogen analog of kotalanol (SN). Here, the binding mechanisms of four representative inhibitors of glucoamylase, SK, DSK, and their two nitrogen analogues, were explored in an integrated modeling study combining molecular dynamics (MD) simulations, binding free energy calculations, and binding free energy decomposition analysis. Our simulations highlight the significant impact of the combination of nitrogen substitution and sulfate anion group. Nitrogen substitution in the five-membered ring leads to the overturning of the polyhydroxylated chain, originating from the shorter bond length of N―C compared with S ― C, while the sulfate anion group restrains the freedom of the polyhydroxylated chain. These cumulative effects are able to significantly change the binding conformation of the inhibitor and substantially impair interactions between the inhibitor and glucosidase. The structural insights obtained in this study are expected to be valuable for increased understanding of the binding mechanism of sulfonium ion glucosidase inhibitors and future design of more potent glucosidase inhibitors.