Tummino Tia A, Iliopoulos-Tsoutsouvas Christos, Braz Joao M, O'Brien Evan S, Stein Reed M, Craik Veronica, Tran Ngan K, Ganapathy Suthakar, Liu Fangyu, Shiimura Yuki, Tong Fei, Ho Thanh C, Radchenko Dmytro S, Moroz Yurii S, Rosado Sian Rodriguez, Bhardwaj Karnika, Benitez Jorge, Liu Yongfeng, Kandasamy Herthana, Normand Claire, Semache Meriem, Sabbagh Laurent, Glenn Isabella, Irwin John J, Kumar Kaavya Krishna, Makriyannis Alexandros, Basbaum Allan I, Shoichet Brian K
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA, 94158, USA.
Nat Commun. 2025 Mar 6;16(1):2237. doi: 10.1038/s41467-025-57136-7.
Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (K = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of G signaling. A cryo-EM structure of '1350 in complex with CB1R-G confirms its predicted docked pose. The lead agonist is strongly analgesic in male mice, with a 2-20-fold therapeutic window over hypolocomotion, sedation, and catalepsy and no observable conditioned place preference. These findings suggest that unique cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from analgesia, supporting the further development of cannabinoids as pain therapeutics.
虚拟库对接可以揭示出与生物靶点结构互补的意外化学类型。为了寻找大麻素-1受体（CB1R）的激动剂，我们对接了7400万个实际分子，并对46个排名靠前的分子进行了从头合成和测试的优先级排序。其中9个通过放射性配体竞争具有活性，命中率为20%。对这些最有效的分子之一（K = 0.7 μM）进行基于结构的优化，得到了“1350”，一种0.95 nM的配体和G信号传导的完全CB1R激动剂。“1350”与CB1R-G复合物的冷冻电镜结构证实了其预测的对接姿势。先导激动剂在雄性小鼠中具有强烈的镇痛作用，与运动减少、镇静和僵住症相比，具有2至20倍的治疗窗口，并且没有可观察到的条件性位置偏爱。这些发现表明，独特的大麻素化学类型可能将典型的大麻素副作用与镇痛作用区分开来，支持将大麻素进一步开发为疼痛治疗药物。
