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Structure. 2014 Aug 5;22(8):1140-1151. doi: 10.1016/j.str.2014.05.017. Epub 2014 Jul 17.

Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.

Author information

1
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.
2
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.
3
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.
4
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.

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.

PMID:
25043551
DOI:
10.1016/j.str.2014.05.017
[Indexed for MEDLINE]
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