Discovery of a Novel 5-HT2A inhibitor by pharmacophore-based virtual screening

The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression. In this study, a potent novel 5-HT2A inhibitor 05245768 with a K-i value of (593.89 +/- 34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction, pharmacophore-based virtual screening, automated molecular docking and pharmacological bioassay). The 5-HT2A receptor showed a negatively charged binding pocket. The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure, which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylatc group of D3.32 at the active site of 5-HT2A.