title: Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.
abstract: The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles.
authors.affiliation: Science for Life Laboratory, Stockholm University, Box 1031, 171 21 Solna, Sweden; Department of Biochemistry and Biophysics, Center for Biomembrane Research, Stockholm University, 106 91 Stockholm, Sweden; Swedish e-Science Research Center, 100 44 Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez
authors.affiliation: USEF Screening Platform-BioFarma Research Group, Centre for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain. Electronic address: pepo.brea@usc.es.
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.affiliation: USEF Screening Platform-BioFarma Research Group, Centre for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Loza
authors.affiliation: Science for Life Laboratory, Stockholm University, Box 1031, 171 21 Solna, Sweden; Department of Biochemistry and Biophysics, Center for Biomembrane Research, Stockholm University, 106 91 Stockholm, Sweden; Swedish e-Science Research Center, 100 44 Stockholm, Sweden. Electronic address: jens.carlsson@dbb.su.se.
authors.forename: Jens
authors.initials: J
authors.lastname: Carlsson
mesh_terms: D000242:Cyclic AMP / Q000378:metabolism; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D058825:Serotonin 5-HT1 Receptor Agonists; D000242:Cyclic AMP