Novel structural insights for drug design of selective 5-HT(2C) inverse agonists from a ligand-biased receptor model.
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 β1 and β2 adrenoceptors. On the basis of ligand-biased homology modeling and docking-scoring calculations, a ritanserin-biased 5-HT(2C) receptor model has been built and used in a highly efficient virtual screening protocol to discriminate specifically 5-HT(2C) inverse agonists in a fuzzy dataset including hundreds of compounds with known experimental values of 5-HT(2C) affinity and activity. The resulting fingerprint of interaction displays hotspots in the third transmembrane α-helix and the second extracellular loop selectively bound by most 5-HT(2C) inverse agonists.
Renault
Nicolas
N
Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie Thérapeutique, EA GRIIOT, Université Nord de France, 3 rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France.
Gohier
Arnaud
A
Chavatte
Philippe
P
Farce
Amaury
A
D000595:Amino Acid Sequence; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008969:Molecular Sequence Data; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D017386:Sequence Homology, Amino Acid; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology*
D008024:Ligands; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists