| First Author | Kaplan AL | Year | 2022 |
| Journal | Nature | Volume | 610 |
| Issue | 7932 | Pages | 582-591 |
| PubMed ID | 36171289 | Mgi Jnum | J:340009 |
| Mgi Id | MGI:7525448 | Doi | 10.1038/s41586-022-05258-z |
| Citation | Kaplan AL, et al. (2022) Bespoke library docking for 5-HT(2A) receptor agonists with antidepressant activity. Nature 610(7932):582-591 |
| abstractText | 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(2A)R) 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(2A)R 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(2A)R agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT(2A)R. 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(2A)R 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. |
