School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China.
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Yangtze Delta Region Academy of Beijing Institute of Technology, Jiaxing 314019, China.
J Med Chem. 2024 Aug 22;67(16):14574-14585. doi: 10.1021/acs.jmedchem.4c01353. Epub 2024 Aug 2.
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the main components of plants, have attracted a significant amount of attention due to their biological activities. This study identified GPR18 as the target of partial agonist CBD activating the p42/p44 MAPK pathway leading to migration of endometrial epithelial cells. Induced fit docking (IFD) showed that the affinity of THC for GPR18 is higher than that of CBD, and molecular dynamics (MD) simulations showed that CBD-GPR18 complexes at 130/200 ns might have stable conformations, potentially activating GPR18 by changing the distances of key residues in its active pocket. In contrast, THC maintains "metastable" conformations, generating a "shrinking space" leading to full agonism of THC by adding mechanical constraints in GPR18's active pocket. Steered molecular dynamics (SMD) revealed GPR18's active pocket was influenced more by CBD's partial agonism compared with THC. This combined IFD-MD-SMD method may be used to explain the mechanism of activation of partial or full agonists of GPR18.
大麻二酚（CBD）和 Δ9-四氢大麻酚（THC）是植物的主要成分，由于其生物活性而引起了广泛关注。本研究确定 GPR18 为部分激动剂 CBD 的作用靶点，CBD 通过激活 p42/p44 MAPK 通路促进子宫内膜上皮细胞迁移。诱导契合对接（IFD）表明，THC 与 GPR18 的亲和力高于 CBD，分子动力学（MD）模拟表明 CBD-GPR18 复合物在 130/200ns 时可能具有稳定的构象，通过改变其活性口袋中关键残基的距离，可能激活 GPR18。相比之下，THC 保持“亚稳定”构象，通过在 GPR18 的活性口袋中增加机械约束，产生“收缩空间”，从而导致 THC 完全激动。定向分子动力学（SMD）揭示了与 THC 相比，CBD 的部分激动作用对 GPR18 的活性口袋影响更大。这种结合 IFD-MD-SMD 的方法可用于解释 GPR18 的部分激动剂或完全激动剂的激活机制。
