Structure-Based Discovery of Selective Serotonin 5-HT1B Receptor Ligands
2014 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 22, no 8, 1140-1151 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 22, no 8, 1140-1151 p.
Biochemistry and Molecular Biology Cell Biology
IdentifiersURN: urn:nbn:se:su:diva-107427DOI: 10.1016/j.str.2014.05.017ISI: 000340488100007OAI: oai:DiVA.org:su-107427DiVA: diva2:748405