Bespoke library docking for 5-HT2A receptor agonists with anti-depressant activity
In: Nature, 2022
academicJournal
Zugriff:
There is much interest in screening ultra-large chemical libraries for ligand discovery, both empirically and computationally(1 2–4). 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 poorly sampled by a general billion-molecule virtual library but 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 synthesis and testing of 17 initial molecules. Four had low μM activities against either the 5-HT(2A) or 5-HT(2B) receptors. Structure-based optimization led to 5-HT(2A)R agonists (R)-69 and (R)-70 with EC(50)s of 41 and 110 nM and unusual signaling kinetics differing from psychedelic 5-HT(2A)R agonists. Cryo-EM structural analysis confirmed the predicted binding mode to the 5-HT(2A)R. The favorable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioral assays. Intriguingly, neither had psychedelic activity, in contrast to classic 5-HT(2A)R agonists, while both had potent anti-depressant activity in mouse models and were equi-efficacious to anti-depressants like fluoxetine at as little as 1/40(th) the dose. Prospects for using bespoke virtual libraries to sample pharmacologically-relevant chemical space will be considered.
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Bespoke library docking for 5-HT2A receptor agonists with anti-depressant activity
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Autor/in / Beteiligte Person: | Kaplan, Anat Levit ; Confair, Danielle N. ; Kim, Kuglae ; Barros-Álvarez, Ximena ; Rodriguiz, Ramona M. ; Yang, Ying ; Kweon, Oh Sang ; Che, Tao ; McCorvy, John ; Kamber, David N. ; Phelan, James P. ; Martins, Luan Carvalho ; Pogorelov, Vladimir M. ; DiBerto, Jeffrey F. ; Slocum, Samuel T. ; Huang, Xi-Ping ; Kumar, Jain Manish ; Robertson, Michael J. ; Panova, Ouliana ; Seven, Alpay B. ; Wetselumn, Q. ; Wetsel, William C. ; Irwin, John J. ; Skiniotis, Georgios ; Shoichet, Brian K. ; Roth, Bryan L. ; Ellman, Jonathan A. |
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Zeitschrift: | Nature, 2022 |
Veröffentlichung: | 2022 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41586-022-05258-z |
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