Faculty Collaboration Database

Bespoke library docking for 5-HT_2A receptor agonists with antidepressant activity. Nature 2022 Oct;610(7932):582-591

Date

09/29/2022

Pubmed ID

36171289

Pubmed Central ID

PMC9996387

DOI

10.1038/s41586-022-05258-z

Scopus ID

2-s2.0-85139098126 (requires institutional sign-in at Scopus site)   198 Citations

Abstract

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally^1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization^5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT_2A receptor (5-HT_2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT_2A or the 5-HT_2B receptors. Structure-based optimization led to the 5-HT_2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT_2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT_2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT_2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.

Author List

Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antidepressive Agents
Cryoelectron Microscopy
Fluoxetine
Hallucinogens
Ligands
Mice
Pyrrolidines
Receptor, Serotonin, 5-HT2A
Small Molecule Libraries