There is much interest in screening ultra-large chemical libraries, both empirically and computationally. Both efforts have focused on readily synthesizable molecules, inevitably leaving many interesting chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines (THPs), a scaffold poorly sampled by a general 1.35 billion-molecule make-on-demand virtual library but well-suited to many aminergic G protein-coupled receptors (GPCRs). Using three inputs, each with many diverse commercially available derivatives, a one pot C–H alkenylation, electrocyclization, and reduction sequence provides the tetrahydropyridine core with up to six sites of side chain derivatization. Restricting ourselves to tetrahydropyridines with MW &lt;350 led to a virtual library of 75 million molecules. Docking these against a model of the serotonin 5-HT2A receptor (5-HT2AR) prioritized hundreds-of-thousands of molecules, of which 17 were initially synthesized and tested. Four had low μM activities against either the 5-HT2A or 5-HT2B receptors; one had weak antagonist activity against human 5-HT2AR. We optimized these leads using a cycle of design, synthesis, and testing for binding and function. This revealed 5-HT2AR agonists (R)-69 and (R)-70 with EC50s of 41 and 110 nM and unusual signaling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-EM structural analysis validated the predicted mode of binding to the 5-HT2AR. The favorable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioral assays. Intriguingly, neither had psychedelic drug-like nor locomotor-stimulating activities, again in contrast to classic psychedelics. Significantly, both had potent antidepressant drug-like actions in a mouse model, matching the effects of fluoxetine (Prozac) at 1/40th the dose. Prospects for using bespoke virtual libraries to deepen sampling of pharmacologically-relevant chemical space will be considered.

Docking a bespoke ultra-large tetrahydropyridine library identifies 5-HT2A agonists with anti-depressant effects

ACS Spring 2022

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