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

T Tia A. Tummino C Christos Iliopoulos-Tsoutsouvas J Joao M. Braz (Department Anatomy, University of California) E Evan S. O’Brien R Reed M. Stein V Veronica Craik N Ngan K. Tran S Suthakar Ganapathy F Fangyu Liu Y Yuki Shiimura F Fei Tong (Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China) T Thanh C. Ho D Dmytro S. Radchenko Y Yurii S. Moroz S Sian Rodriguez Rosado K Karnika Bhardwaj J Jorge Benitez Y Yongfeng Liu (State Key Laboratory of Silicon Materials and School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China) H Herthana Kandasamy C Claire Normand M Meriem Semache L Laurent Sabbagh I Isabella Glenn J John J. Irwin K Kaavya Krishna Kumar A Alexandros Makriyannis A Allan I. Basbaum (Department Anatomy, University of California) B Brian K. Shoichet

Abstract

Abstract 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.

Article Details

Volume / Issue Vol. 16, Issue 1
Published March 06, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (28)

T

Tia A. Tummino

C

Christos Iliopoulos-Tsoutsouvas

J

Joao M. Braz

Department Anatomy, University of California

E

Evan S. O’Brien

R

Reed M. Stein

V

Veronica Craik

N

Ngan K. Tran

S

Suthakar Ganapathy

F

Fangyu Liu

Y

Yuki Shiimura

F

Fei Tong

Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China

T

Thanh C. Ho

D

Dmytro S. Radchenko

Y

Yurii S. Moroz

S

Sian Rodriguez Rosado

K

Karnika Bhardwaj

J

Jorge Benitez

Y

Yongfeng Liu

State Key Laboratory of Silicon Materials and School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China

H

Herthana Kandasamy

C

Claire Normand

M

Meriem Semache

L

Laurent Sabbagh

I

Isabella Glenn

J

John J. Irwin

K

Kaavya Krishna Kumar

A

Alexandros Makriyannis

A

Allan I. Basbaum

Department Anatomy, University of California

B

Brian K. Shoichet