Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter

Author:

Singh IshaORCID,Seth AnubhaORCID,Billesbølle Christian B.,Braz Joao,Rodriguiz Ramona M.ORCID,Roy KasturiORCID,Bekele BethlehemORCID,Craik VeronicaORCID,Huang Xi-PingORCID,Boytsov Danila,Lak Parnian,O’Donnell HenryORCID,Sandtner WalterORCID,Roth Bryan L.,Basbaum Allan I.ORCID,Wetsel William C.ORCID,Manglik AashishORCID,Shoichet Brian K.ORCID,Rudnick GaryORCID

Abstract

SUMMARYThe serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has an unusual anti-depressant profile and stabilizes the inward-open conformation. Unfortunately, ibogaine is promiscuous and cardiotoxic, limiting understanding of inward-open state ligands. We computationally docked over 200 million small molecules against the ibogaine stabilized inward-open state of SERT. Thirty-six top-ranking compounds were synthesized and thirteen inhibited with potencies ranging from 29 to 5000 nM. Structure-based optimization led to two novel inhibitors with Ki values down to 3 nM. The new molecules stabilized an outward-closed state of the transporter and had little activity against off-targets. A cryo-EM structure of one of these bound to SERT confirmed the predicted geometry. In mouse behavioral assays, both had anxiolytic and anti-depressant activity, with potencies up to 200 better than fluoxetine.

Publisher

Cold Spring Harbor Laboratory

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