College of Science, Beihua University, Jilin 132013, China.
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China.
Int J Mol Sci. 2024 Oct 20;25(20):11290. doi: 10.3390/ijms252011290.
Polyacetylene (PA) compounds, as natural products, exhibit remarkable properties and distinctive chemical activities. Three structurally similar C14-PA compounds-Echinophorin D, Echinophorin B, and Echinophorin A-extracted from plants demonstrate varying biological activities on the Transient Receptor Potential Channel A1 (TRPA1) protein, which belongs to the TRP (Transient Receptor Potential) family. In the current study, we investigated the binding modes of these three PA compounds with TRPA1 using molecular dynamics (MD), molecular docking, binding free energy calculations, and quantum mechanics/molecular mechanics (QM/MM) methods. Initially, a putative binding site (site-II) in TRPA1 was identified for these compounds; Echinophorin B was found to stabilize the upward A-loop of TRPA1, which is critical for its activation. Furthermore, the binding affinity calculations of PA compounds through molecular fragment decomposition indicate that the arrangement of two triple bonds and one double bond in C14-PA compounds is vital for regulating TRPA1 bioactivity. Additionally, the lipophilic and electronic properties of the three molecules were analyzed in relation to binding affinity, establishing a correlation between TRPA1 activity and these molecular properties.
聚乙炔（PA）化合物作为天然产物，表现出显著的性质和独特的化学活性。从植物中提取的三种结构相似的 C14-PA 化合物——Echinophorin D、Echinophorin B 和 Echinophorin A——对属于 TRP（瞬时受体电位）家族的瞬时受体电位通道 A1（TRPA1）蛋白表现出不同的生物活性。在本研究中，我们使用分子动力学（MD）、分子对接、结合自由能计算和量子力学/分子力学（QM/MM）方法研究了这三种 PA 化合物与 TRPA1 的结合模式。最初，在 TRPA1 中确定了这些化合物的一个假定结合位点（位点-II）；Echinophorin B 被发现稳定了 TRPA1 的向上 A 环，这对其激活至关重要。此外，通过分子片段分解对 PA 化合物的结合亲和力计算表明，C14-PA 化合物中两个三键和一个双键的排列对调节 TRPA1 生物活性至关重要。此外，还分析了这三个分子的疏水性和电子性质与结合亲和力的关系，确定了 TRPA1 活性与这些分子性质之间的相关性。
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