A Prospective Cross-Screening Study on G-Protein-Coupled Receptors: Lessons Learned in Virtual Compound Library Design

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5311-5325
• 全文大小：664K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

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 尾-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.