Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches.
Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches.
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绿原酸与AMPA受体相互作用机制的计算机结构研究。
DOI：
10.3390/molecules27113394
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发表时间：
2022-05-25
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影响因子：
--
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绿原酸（Chlorogenic acid，CGA）是金银花、甘草等天然植物药的重要代谢产物，具有较强的镇痛作用。然而，CGA缓解慢性疼痛的机制仍不清楚。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor，AMPAR）是介导快速兴奋性突触传递的主要离子型谷氨酸受体，其谷氨酸离子型受体AMPA型亚单位1（GluA 1）在伤害性信息传递中起关键作用。本研究采用Western blot、表面等离子体共振（SPR）和分子模拟技术，探讨了CGA与AMPAR相互作用缓解慢性疼痛的机制。结果表明，随着CGA浓度的增加（0、50、100和200 μM），GluA 1蛋白表达水平呈依赖性下降。SPR分析表明CGA可以直接与GluA 1结合（KD = 496 μM）。此外，CGA与GluA 1形成稳定的结合相互作用，这是通过分子动力学（MD）模拟验证。CGA与GluA 1之间的结合自由能为-39.803 ± 14.772 kJ/mol，其中货车范德华相互作用和静电相互作用是GluA 1-CGA结合的主要贡献者，并确定了在结合相互作用中发挥关键作用的关键残基（瓦尔-32、Glu-33、Ala-36、Glu-37、Leu-48）。本研究首次揭示了CGA与GluA 1之间稳定相互作用形成结合复合物以缓解慢性疼痛的结构基础。该研究为了解慢性疼痛的治疗提供了结构基础，对未来新型药物分子的设计具有重要价值。
Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.
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