物理化学学报 >> 2012, Vol. 28 >> Issue (09): 2191-2201.doi: 10.3866/PKU.WHXB201207063

生物物理化学 上一篇    下一篇

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

罗芳1, 高剑1, 成元华1,2, 崔巍1, 计明娟1   

  1. 1. 中国科学院研究生院化学与化学工程学院, 北京 100049;
    2. 清华大学化学系, 教育部有机光电分子工程重点实验室, 北京 100084
  • 收稿日期:2012-05-07 修回日期:2012-07-06 发布日期:2012-08-02
  • 通讯作者: 计明娟 E-mail:jmj@gucas.ac.cn
  • 基金资助:

    国家自然科学基金(21173264), 科技部重大专项(2009ZX09501-011)和中国科学院知识创新工程基金(ZNWH-2011-011)资助项目

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

LUO Fang1, GAO Jian1, CHENG Yuan-Hua1,2, CUI Wei1, JI Ming-Juan1   

  1. 1. College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. China;
    2. Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
  • Received:2012-05-07 Revised:2012-07-06 Published:2012-08-02
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (21173264), National Science and Technology Major Special Project of China (2009ZX09501-011), and Foundation of Knowledge Innovative Engineering of Chinese Academy of Sciences (ZNWH-2011-011).

摘要:

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.

关键词: 锍离子, 葡萄糖苷酶抑制剂, 分子动力学模拟, 自由能计算, 自由能分解

Abstract:

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.

Key words: Sulfonium ion, Glucoamylase inhibitor, Molecular dynamic simulation, Free energy calculation, Free energy decomposition

MSC2000: 

  • O641