9pns
Structure of human serotonin transporter bound to small molecule zPZd in lipid nanodisc and NaCl
Structural highlights
FunctionSC6A4_HUMAN Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.[1] [2] [3] Publication Abstract from PubMedPolypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (alpha(2A)/SERT, MOR/SERT, and alpha(2A)/MOR), we sought analgesic compounds. Both the alpha(2A)/SERT and SERT/MOR campaigns led to dual binders with low muM to high nM activities with high hit rates; tetrahydropyridines from the alpha(2A)/SERT campaign were also active against 5-HT(2A). However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent alpha(2A)/SERT compound ('z7149) was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT(2A) activities. This study reveals both advantages and challenges of docking for polypharmacology. Large Library Docking for Polypharmacology.,Wu Y, Vigneron S, Braz J, Srinivasan K, Fink EA, Huang XP, Xu X, Huebner H, Kim JY, Wang J, Pfeiffer T, Sakamoto K, Radchenko DS, Rodriguiz RM, Moroz YS, Irwin JJ, Gmeiner P, Billesboelle C, Roth BL, Basbaum AI, Manglik A, Wetsel WC, Shoichet BK J Med Chem. 2026 Feb 19. doi: 10.1021/acs.jmedchem.5c03810. PMID:41712624[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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