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A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.

Sanders, Marijn P A; Roumen, Luc; van der Horst, Eelke; Lane, J Robert; Vischer, Henry F; van Offenbeek, Jody; de Vries, Henk; Verhoeven, Stefan; Chow, Ken Y; Verkaar, Folkert; Beukers, Margot W; McGuire, Ross; Leurs, Rob; Ijzerman, Adriaan P; de Vlieg, Jacob; de Esch, Iwan J P; Zaman, Guido J R; Klomp, Jan P G; Bender, Andreas; de Graaf, Chris


Marijn P A Sanders

Luc Roumen

Eelke van der Horst

J Robert Lane

Henry F Vischer

Jody van Offenbeek

Henk de Vries

Stefan Verhoeven

Ken Y Chow

Folkert Verkaar

Margot W Beukers

Ross McGuire

Rob Leurs

Adriaan P Ijzerman

Jacob de Vlieg

Iwan J P de Esch

Guido J R Zaman

Jan P G Klomp

Andreas Bender

Chris de Graaf


We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the ?-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts.


Sanders, M. P. A., Roumen, L., van der Horst, E., Lane, J. R., Vischer, H. F., van Offenbeek, J., …de Graaf, C. (2012). A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design. Journal of Medicinal Chemistry, 55(11), 5311-5325.

Journal Article Type Article
Acceptance Date Feb 28, 2012
Online Publication Date May 23, 2012
Publication Date Jun 14, 2012
Deposit Date Apr 22, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 55
Issue 11
Pages 5311-5325
Public URL
Publisher URL

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