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.

Manetti, F., Faure, H., Roudaut, H., Gorojankina, T., Traiffort, E., Schoenfelder, A., et al. (2010). Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonists. MOLECULAR PHARMACOLOGY, 78(4), 658-665 [10.1124/mol.110.065102].

Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonists

MANETTI, FABRIZIO;TADDEI, MAURIZIO;
2010

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.
Manetti, F., Faure, H., Roudaut, H., Gorojankina, T., Traiffort, E., Schoenfelder, A., et al. (2010). Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonists. MOLECULAR PHARMACOLOGY, 78(4), 658-665 [10.1124/mol.110.065102].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/22203
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