The development and validation of a novel virtual screening cascade protocol to identify potential serotonin 5-HT(7)R antagonists

Rafał Kurczab; Mateusz Nowak; Zdzisław Chilmonczyk; Ingebrigt Sylte; Andrzej J Bojarski

doi:10.1016/j.bmcl.2010.03.012

The development and validation of a novel virtual screening cascade protocol to identify potential serotonin 5-HT(7)R antagonists

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2465-8. doi: 10.1016/j.bmcl.2010.03.012. Epub 2010 Mar 6.

Authors

Rafał Kurczab¹, Mateusz Nowak, Zdzisław Chilmonczyk, Ingebrigt Sylte, Andrzej J Bojarski

Affiliation

¹ Institute of Pharmacology, Polish Academy of Sciences, Smetna, Kraków, Poland.

PMID: 20346662
DOI: 10.1016/j.bmcl.2010.03.012

Abstract

In an attempt to identify new ligands for the 5-HT(7) receptor (5-HT(7)R), we developed and tested a hierarchical multi-step strategy of virtual screening (VS) based on two-dimensional (2D) pharmacophore similarity, physicochemical scalar descriptors, an ADME/Tox filter, three-dimensional (3D) pharmacophore searches and a docking protocol. Six chemical classes of 5-HT(7)R antagonists were used as query structures in a double-path virtual screening scheme. The Enamine screening database, consisting of approximately 730,000 commercially available drug-like compounds, was adopted and used as a source of structures. A biological evaluation of 26 finally selected virtual hits resulted in finding two benzodioxane derivatives with significant affinity (K(i)=197 and 265 nM). The approach described in this case study can be easily used as a general rational drug design tool for other biological targets.

Publication types

Research Support, Non-U.S. Gov't
Validation Study

MeSH terms

Models, Molecular
Receptors, Serotonin / drug effects*
Serotonin Antagonists / pharmacology*

Substances

Receptors, Serotonin
Serotonin Antagonists
serotonin 7 receptor