In order to find potential new structures of 5-HT₇R ligands we used previously developed and tested hierarchical multistage strategy of virtual screening [1]. This workflow was based on two-dimensional (2D) pharmacophore similarity searching, physicochemical scalar descriptors, ADME/Tox filter, three-dimensional (3D) pharmacophore searches and docking protocol. Additionally, in order to increase chemotype's diversity of virtual hits, the chemical topology and pharmacophore topology fingerprints have been applied at the stage of similarity search. The six chemical classes of 5-HT₇R antagonists [2] were used as a query structures in double-path virtual screening scheme. The commercially available resources, offered by the ChemBridge [3] and ChemDiv [4] companies, have been adopted and used as a molecular screening space consisting of approximately 1 300 000 compounds. Finally, the best virtual hits were selected and acquired in order to determine their affinity for 5-HT₇ receptor. The binding mode of selected virtual hits are shown in comparison to those of known antagonists [2].

This study was partly supported by a grant PNRF-103-AI-1/07 from Norway through the Norwegian Financial Mechanism.

References:
[1] R. Kurczab, M. Nowak, Z. Chilmonczyk, I. Sylte, A. J. Bojarski, Bioorg. Med. Chem. Lett., doi:10.1016/j.bmcl.2010.03.012.
[2] M. Kołaczkowski, M. Nowak, M. Pawłowski, A. J. Bojarski J. Med. Chem. 2006, 49, 6732.
[3] http://www.chembridge.com/
[4] http://www.chemdiv.com/

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