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

Abstract

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 β-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.

Citation

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. https://doi.org/10.1021/jm300280e

• 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
• DOI: https://doi.org/10.1021/jm300280e
• Public URL: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22563707&retmode=ref&cmd=prlinks
• Publisher URL: https://pubs.acs.org/doi/abs/10.1021/jm300280e