Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists

The serotonin 5-HT2A receptors are widely distributed throughout the central and the peripheral nervous system where they play a key role in many physiological functions. Abnormal activity of 5-HT2A receptors is associated with various neurological disorders, such as depression, schizophrenia, anxiety, and Parkinson disease. In order to analyze 3D-structure of the pharmacophore as well as binding kinetics of 5-HT2A-R antagonists, we have combined ligand and structure based approaches. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study in combination with molecular docking and molecular dynamic (MD) simulation was used to identify key substituents responsible for high binding affinity and selectivity of 5-HT2A antagonists. The study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and CHEMBL240876 derivates. We have obtained three different inactive, antagonistbound, conformations of this receptor by using the 50ns long MD simulations with each cluster representative. Subsequently, these conformations were used as templates for docking studies in order to find virtually bioactive conformations of ligands. Selected virtually bioactive conformations were used for calculation of specific molecular descriptors (Grid Independent Descriptors- GRIND) and 3D-QSAR model building. The 3D-QSAR approach was used to select the most influential variables which were used for clarifying the structural features required for 5-HT2A antagonists. The reliability and predictive power of the model was assessed using an external test set compounds and showed reasonable external predictability. The study provides valuable information about the key structural features that are required in the rational drug design of novel 5-HT2A antagonists