Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia.
Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia.
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桦木酸与α-葡萄糖苷酶的结合相互作用及其对餐后高血糖的缓解
DOI：
10.3390/molecules27082517
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发表时间：
2022-04-13
期刊：
影响因子：
4.6
通讯作者：
Wu, Qingping
中科院分区：
文献类型：
--
作者：
Chen, Shaodan;Lin, Bing;Gu, Jiangyong;Yong, Tianqiao;Gao, Xiong;Xie, Yizhen;Xiao, Chun;Zhan, Janis Yaxian;Wu, Qingping
关键词：
抑制肠道α-葡萄糖苷酶可有效控制餐后高血糖，用于2型糖尿病（T2 DM）治疗。本文报道了桦木酸（betulinic acid，BA）与α-葡萄糖苷酶的结合作用及其对餐后高血糖的缓解作用。BA对α-葡萄糖苷酶有较强的抑制作用，IC_（50）为16.83 ± 1.16 μM。更重要的是，它与阿卡波糖显示出协同抑制作用。通过动力学分析、表面等离子体共振（SPR）检测、分子对接、分子动力学（MD）模拟和结合自由能计算等方法研究了其抑制机理。BA对α-葡萄糖苷酶表现出非竞争性抑制作用。SPR结果表明，该酶与α-葡萄糖苷酶有很强的亲和性，其平衡解离常数（KD）为5.529 × 10−5 M，解离速度较慢。分子对接和分子动力学模拟表明，BA主要通过货车范德华力和氢键作用与α-葡萄糖苷酶活性位点结合，改变了α-葡萄糖苷酶的微环境和二级结构。自由能分析表明，α-葡萄糖苷酶结合口袋中的PHE 155、PHE 175、HIE 277、PHE 298、GLU 302、TRY 311和ASP 347等氨基酸残基与BA的结合力较强，而LYS 153、ARG 210、ARG 310、ARG 354和ARG 437等氨基酸残基对BA与α-葡萄糖苷酶的结合力有负贡献。口服BA明显减轻了小鼠餐后血糖波动。本研究为BA作为功能性食品和天然药物控制餐后高血糖提供了新的思路。
Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC50 value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (KD) value of 5.529 × 10−5 M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.
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