@article {Manetti658, author = {Fabrizio Manetti and Helene Faure and Hermine Roudaut and Tatiana Gorojankina and Elisabeth Traiffort and Angele Schoenfelder and Andre Mann and Antonio Solinas and Maurizio Taddei and Martial Ruat}, title = {Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists}, volume = {78}, number = {4}, pages = {658--665}, year = {2010}, doi = {10.1124/mol.110.065102}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/78/4/658}, eprint = {https://molpharm.aspetjournals.org/content/78/4/658.full.pdf}, journal = {Molecular Pharmacology} }