The 5-HT₆ serotonin receptor (5-HT₆R) is involved in regulation of variety of physiological processes affecting i.e. cognition, food intake and mood. Therefore 5-HT₆R ligands are likely to be effective in therapy of various forms of dementia, schizophrenia, obesity or depression. However, rational design of new 5-HT₆R ligands is difficult because of limited knowledge about spatial configuration of 5‑HT₆R binding site. Homology modeling is a method of choice in such a case. The homology model of 5-HT₆R was built using induced fit docking protocol, integrated into Schrödinger Suite 2009 software. This method seems to be very useful in homology modeling of GPCRs since it combines flexible ligand docking with protein structure prediction and side chains refinement [1]. Fair sequence homology between serotonin 5-HT₆ and adrenergic β₂ receptors, both of which belong to the same GPCR subfamily, influenced the choice of the latter receptor structure as a template for homology modeling [2]. For this purpose, 14 selective ligands of 5-HT₆R with lowest possible conformational flexibility were used [3]. All of these ligands were docked to each obtained model to select the receptors which properly describe interactions in the whole group of ligands. During further validation, a set of ligands with known 5-HT₆R affinity (active and non-active) were automatically docked to the selected models in order to verify their usefulness in a virtual screening procedure. Successful verification allowed to carry out the virtual screening trial in which a database of over 17000 compounds has been searched. In order to establish enrichment factor several 5-HT₆R high affinity ligands were enclosed within the database [4].

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