Details
- Autor(en) / Beteiligte
- Titel
- Structure-based discovery of potent and selective melatonin receptor agonists
- Ist Teil von
- eLife, 2020-03, Vol.9
- Ort / Verlag
- England: eLife Sciences Publications Ltd
- Erscheinungsjahr
- 2020
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Melatonin receptors MT and MT are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound reaching EC of 0.36 nM. Six of these molecules displayed selectivity for MT over MT . Moreover, two most potent agonists, including and a close derivative of melatonin, , had dramatically reduced arrestin recruitment at MT , while compound was devoid of G signaling at MT , implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2050-084XeISSN: 2050-084XDOI: 10.7554/elife.53779Titel-ID: cdi_doaj_primary_oai_doaj_org_article_ae3b26d29f104825bba96ae407a6e98e
- Format
- –
- Schlagworte
- Agonists, Arrestin, biased signaling, Binding Sites, Biochemistry and Chemical Biology, Circadian rhythm, Circadian rhythms, Computational and Systems Biology, Diabetes mellitus, Drug Discovery - methods, Drug Evaluation, Preclinical - methods, Eye movements, GPCR, Humans, Insomnia, Ligands, Melatonin, Melatonin receptors, Mood, Mutation, Proteins, Receptor, Melatonin, MT1 - agonists, Receptor, Melatonin, MT2 - agonists, Receptors, Melatonin - agonists, Sleep, Structure-Activity Relationship, virtual ligand screening