Scholarlink

<p>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<sub>i</sub> = 0.7 µM) leads to ‘1350, a 0.95 nM ligand and a full CB1R agonist of G<sub>i/o</sub> signaling. A cryo-EM structure of ‘1350 in complex with CB1R-G<sub>i1</sub> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月6日

查看全文
  • Tia A. Tummino,
  • Christos Iliopoulos-Tsoutsouvas,
  • Joao M. Braz,
  • Evan S. O’Brien,
  • Reed M. Stein,
  • Veronica Craik,
  • Ngan K. Tran,
  • Suthakar Ganapathy,
  • Fangyu Liu,
  • Yuki Shiimura,
  • Fei Tong,
  • Thanh C. Ho,
  • Dmytro S. Radchenko,
  • Yurii S. Moroz,
  • Sian Rodriguez Rosado,
  • Karnika Bhardwaj,
  • Jorge Benitez,
  • Yongfeng Liu,
  • Herthana Kandasamy,
  • Claire Normand,
  • Meriem Semache,
  • Laurent Sabbagh,
  • Isabella Glenn,
  • John J. Irwin,
  • Kaavya Krishna Kumar,
  • Alexandros Makriyannis,
  • Allan I. Basbaum,
  • Brian K. Shoichet

摘要

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 (Ki = 0.7 µM) leads to ‘1350, a 0.95 nM ligand and a full CB1R agonist of Gi/o signaling. A cryo-EM structure of ‘1350 in complex with CB1R-Gi1 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.