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
{"title":"Large library docking for cannabinoid-1 receptor agonists with reduced side effects.","authors":"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","doi":"10.1101/2023.02.27.530254","DOIUrl":null,"url":null,"abstract":"<p><p>Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.</p>","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"1 1","pages":""},"PeriodicalIF":0.3000,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849508/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Derrida Today","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.02.27.530254","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"0","JCRName":"PHILOSOPHY","Score":null,"Total":0}
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Abstract
Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.
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