Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity.

Journal Article (Journal Article)

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. 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 derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR 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-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. 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-HT2AR 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.

Full Text

Duke Authors

Cited Authors

  • 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, X-P; Kumar, JM; Robertson, MJ; Panova, O; Seven, AB; Wetsel, AQ; Wetsel, WC; Irwin, JJ; Skiniotis, G; Shoichet, BK; Roth, BL; Ellman, JA

Published Date

  • October 2022

Published In

Volume / Issue

  • 610 / 7932

Start / End Page

  • 582 - 591

PubMed ID

  • 36171289

Pubmed Central ID

  • PMC9996387

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/s41586-022-05258-z


  • eng

Conference Location

  • England