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

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

LUO Fang ¹ ,
GAO Jian ¹ ,
CHENG Yuan-Hua ^1,2 ,
CUI Wei ¹ ,
JI Ming-Juan ^1,

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: 7 May 2012
Available Online: 6 July 2012
Fund Project: 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)

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.
- Sulfonium ion,
- Glucoamylase inhibitor,
- Molecular dynamic simulation,
- Free energy calculation,
- Free energy decomposition
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