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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine A2 Receptor Agonists / chemistry
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Adenosine A2 Receptor Antagonists / chemistry
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Adrenergic beta-2 Receptor Agonists / chemistry
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Adrenergic beta-2 Receptor Antagonists / chemistry
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Databases, Factual*
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Drug Design*
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Drug Partial Agonism
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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Ligands
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Models, Molecular*
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Molecular Structure
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Phosphodiesterase 5 Inhibitors / chemistry
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Piperazines / chemistry
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Piperazines / metabolism
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Purines / chemistry
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Purines / metabolism
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Quantitative Structure-Activity Relationship*
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Radioligand Assay
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Receptors, Adenosine A2 / chemistry*
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Receptors, Adenosine A2 / metabolism
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Receptors, Adrenergic, beta-2 / chemistry*
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Receptors, Adrenergic, beta-2 / metabolism
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Receptors, Lysosphingolipid / agonists
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Receptors, Lysosphingolipid / chemistry*
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Receptors, Lysosphingolipid / metabolism
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Sildenafil Citrate
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Stochastic Processes
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Sulfones / chemistry
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Sulfones / metabolism
Substances
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Adenosine A2 Receptor Agonists
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Adenosine A2 Receptor Antagonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-2 Receptor Antagonists
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Ligands
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Phosphodiesterase 5 Inhibitors
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Piperazines
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Purines
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Receptors, Adenosine A2
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Receptors, Adrenergic, beta-2
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Receptors, Lysosphingolipid
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Sulfones
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Sildenafil Citrate