Novel structural insights for drug design of selective 5-HT2C inverse agonists from a ligand-biased receptor model

作者：Renault Nicolas; Gohier Arnaud; Chavatte Philippe; Farce Amaury^*

来源：European Journal of Medicinal Chemistry, 2010, 45(11): 5086-5099.

DOI：10.1016/j.ejmech.2010.08.018

• 5-HT2C inverse agonists
• Ligand-biased homology modeling
• Pharmacophore
• Docking-scoring
• Virtual ligand screening

Structure-based design of compounds targeting monoamine receptors, within the class-A G-protein coupled receptors, has been enriched by the recent crystallization of the beta 1 and beta 2 adrenoceptors. On the basis of ligand-biased homology modeling and docking-scoring calculations, a ritanserin-biased 5-HT2C receptor model has been built and used in a highly efficient virtual screening protocol to discriminate specifically 5-HT2C inverse agonists in a fuzzy dataset including hundreds of compounds with known experimental values of 5-HT2C affinity and activity. The resulting fingerprint of interaction displays hotspots in the third transmembrane a-helix and the second extracellular loop selectively bound by most 5-HT2C inverse agonists.

• 出版日期2010-11