Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5844
DC FieldValueLanguage
dc.contributor.authorManetti, Fabrizioen_us
dc.contributor.authorFaure, Hen_us
dc.contributor.authorRoudaut, Hen_us
dc.contributor.authorGorojankina, Ten_us
dc.contributor.authorTraiffort, Een_us
dc.contributor.authorSchoenfelder, Aen_us
dc.contributor.authorMann, Aen_us
dc.contributor.authorSolinas, Aen_us
dc.contributor.authorTaddei, Maurizioen_us
dc.contributor.authorRuat, M.en_us
dc.date.accessioned2021-03-30T15:55:34Z-
dc.date.available2021-03-30T15:55:34Z-
dc.date.issued2010-
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/20.500.12779/5844-
dc.description36177en_US
dc.description.abstractThe seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5- trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5- trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)- 5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3, 3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.en_US
dc.language.isoenen_US
dc.relationNoneen_US
dc.relation.ispartofMOLECULAR PHARMACOLOGYen_US
dc.titleVirtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonistsen_US
dc.typeArticleen_US
dc.identifier.doi10.1124/mol.110.065102en_US
dc.identifier.pmid20664000en_US
dc.identifier.scopus2-s2.0-77957245263en_US
dc.identifier.isiWOS:000281910200014en_US
dc.relation.volume78en_US
dc.relation.issue4en_US
dc.description.firstpage658en_US
dc.description.lastpage665en_US
dc.description.thirdmissionNot applicableen_US
item.cerifentitytypePublications-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypeArticle-
item.fulltextNo Fulltext-
crisitem.author.orcid0000-0002-9598-2339-
crisitem.author.orcid0000-0001-8660-7580-
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