Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists

Serotonin 5-HT2A receptors (5-HT2AR) are highly expressed in human prefrontal cortex, essential for learning and cognition [1]. Consequently, antagonists of these receptors are effective in treatment of various neuropsychiatric disorders, such as depression, insomnia, schizophrenia, anxiety, and cent progress in molecular modelling studies has led to significant success in drug discovery using ligand and target-based methods. To design novel potent 5-HT2AR antagonists, we report a strategy of combining three-dimensional quantitative structure-activity relationship (3DQSAR) modelling with molecular docking and molecular dynamic (MD) simulation. Based on the common structural features, data set of 75 compounds was divided into three clusters. Firstly, MD simulations were carried out for each cluster representative in complex with 5-HT2AR, providing important molecular level insight into their structure and dynamics. Afterward, to provide more accurate information about binding modes in the active site of the receptor, obtained conformations were used for docking studies and generation of the virtually bioactive conformations of all studied ligands. In addition, 3D-QSAR study, utilizing selected conformers, was carried out to gain further insights into the structural requirements that affect their antagonistic activity. Besides, some commercially available 5-HT2AR antagonists were examined through in vitro PAMPA essay, as well as in silico computational methods not only to improve BBB permeability of new designed compounds, but also to establish promising tool to study their membrane permeability in detail. Overall, these and future results will provide new methodologies that could be used as guidelines for rational drug design of novel 5-HT2AR antagonists