identification of novel 5-HT antagonists supported with ligand- and target-based drug design methodologies.

A wide range of neuropsychological disorders is caused by serotonin 5-HT receptor (5-HTR) malfunction. Therefore, this receptor had been frequently used as target in CNS drug research. To design novel potent 5-HTR antagonists, we have combined ligand-based and target-based approaches. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and ChEMBL240876 derivatives. By performing the 50 ns long molecular dynamic simulations with each cluster representative in complex with 5-HT receptor, we have obtained virtually bioactive conformations of the ligands and three different antagonist-bound, inactive, conformations of the 5-HTR. These three 5-HTR conformations were further used for docking studies and generation of the bioactive conformations of the data set ligands in each cluster. Subsequently, selected conformers were used for 3D-Quantitative Structure Activity Relationship (3D-QSAR) modelling and pharmacophore analysis. The reliability and predictive power of the created model was assessed using an external test set compounds and showed reasonable external predictability. Statistically significant variables were used to define the most important structural features required for 5-HT antagonistic activity. Conclusions obtained from performed ligand-based (3D-QSAR) and target-based (molecular docking and molecular dynamics) methods were compiled and used as guidelines for rational drug design of novel 5-HTR antagonists.Communicated by Ramaswamy H. Sarma.