Journal of medicinal chemistry, 2012-06, Vol.55 (11), p.5311-5325
- 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
2012
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- Autor(en) / Beteiligte
- 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
- Titel
- A Prospective Cross-Screening Study on G-Protein-Coupled Receptors: Lessons Learned in Virtual Compound Library Design
- Ist Teil von
- Journal of medicinal chemistry, 2012-06, Vol.55 (11), p.5311-5325
- Ort / Verlag
- United States: American Chemical Society
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 A2A 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2623eISSN: 1520-4804DOI: 10.1021/jm300280eTitel-ID: cdi_proquest_miscellaneous_1020834608
- Format
- –
- Schlagworte
- Adenosine A2 Receptor Agonists - chemistry, Adenosine A2 Receptor Antagonists - chemistry, Adrenergic beta-2 Receptor Agonists - chemistry, Adrenergic beta-2 Receptor Antagonists - chemistry, Animals, CHO Cells, Cricetinae, Cricetulus, Databases, Factual, Drug Design, Drug Partial Agonism, HEK293 Cells, High-Throughput Screening Assays, Humans, Ligands, Models, Molecular, Molecular Structure, Phosphodiesterase 5 Inhibitors - chemistry, Piperazines - chemistry, Piperazines - metabolism, Purines - chemistry, Purines - metabolism, Quantitative Structure-Activity Relationship, Radioligand Assay, Receptors, Adenosine A2 - chemistry, Receptors, Adenosine A2 - metabolism, Receptors, Adrenergic, beta-2 - chemistry, Receptors, Adrenergic, beta-2 - metabolism, Receptors, Lysosphingolipid - agonists, Receptors, Lysosphingolipid - chemistry, Receptors, Lysosphingolipid - metabolism, Sildenafil Citrate, Stochastic Processes, Sulfones - chemistry, Sulfones - metabolism