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

引用本文: 罗芳, 高剑, 成元华, 崔巍, 计明娟. 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[J]. 物理化学学报, doi: 10.3866/PKU.WHXB201207063 shu

Citation: LUO Fang, GAO Jian, CHENG Yuan-Hua, CUI Wei, JI Ming-Juan. Interaction Mechanisms of Inhibitors of Glucoamylase by Molecular Dynamics Simulations and Free Energy Calculations[J]. Acta Physico-Chimica Sinica, doi: 10.3866/PKU.WHXB201207063 shu

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,

基金项目:
国家自然科学基金(21173264) (21173264)

科技部重大专项(2009ZX09501-011) (2009ZX09501-011)

中国科学院知识创新工程基金(ZNWH-2011-011)资助项目 (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:

English

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

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 Date: 07 May 2012
Available Online: 02 August 2012
Fund Project:
国家自然科学基金(21173264)

科技部重大专项(2009ZX09501-011)

中国科学院知识创新工程基金(ZNWH-2011-011)资助项目

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:

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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

English

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

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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

English

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

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs