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

Abstract 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.