Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter
Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter
SUMMARY The 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.
Craik Veronica、Seth Anubha、Basbaum Allan I.、Manglik Aashish、Huang Xi-Ping、Rudnick Gary、Roth Bryan L.、Braz Joao、Shoichet Brian K.、Sandtner Walter、Billesb?lle Christian B.、Lak Parnian、Bekele Bethlehem、Rodriguiz Ramona M.、Singh Isha、Boytsov Danila、Wetsel William C.、O?ˉDonnell Henry、Roy Kasturi
Department of Anatomy, University of California San FranciscoDepartment of Pharmacology, Yale University School of MedicineDepartment of Anatomy, University of California San FranciscoDepartment of Pharmaceutical Chemistry, University of California San Francisco||Department of Anesthesia and Perioperative Care, University of CaliforniaDepartment of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel HillDepartment of Pharmacology, Yale University School of MedicineDepartment of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill||Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina Chapel HillDepartment of Anatomy, University of California San FranciscoDepartment of Pharmaceutical Chemistry, University of California San FranciscoInstitute of Pharmacology, Center for Physiology and Pharmacology, Medical University of ViennaDepartment of Pharmaceutical Chemistry, University of California San FranciscoDepartment of Pharmaceutical Chemistry, University of California San FranciscoDepartment of Pharmacology, Yale University School of MedicineDepartments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical CenterDepartment of Pharmaceutical Chemistry, University of California San FranciscoInstitute of Pharmacology, Center for Physiology and Pharmacology, Medical University of ViennaDepartments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical CenterDepartment of Pharmaceutical Chemistry, University of California San FranciscoDepartment of Pharmacology, Yale University School of Medicine
药学基础医学神经病学、精神病学
Craik Veronica,Seth Anubha,Basbaum Allan I.,Manglik Aashish,Huang Xi-Ping,Rudnick Gary,Roth Bryan L.,Braz Joao,Shoichet Brian K.,Sandtner Walter,Billesb?lle Christian B.,Lak Parnian,Bekele Bethlehem,Rodriguiz Ramona M.,Singh Isha,Boytsov Danila,Wetsel William C.,O?ˉDonnell Henry,Roy Kasturi.Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter[EB/OL].(2025-03-28)[2025-05-16].https://www.biorxiv.org/content/10.1101/2022.06.13.495991.点此复制
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