title: A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.
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.
authors.affiliation: Computational Drug Discovery Group, Radboud University Nijmegen Medical Centre, Geert Grooteplein, Nijmegen, The Netherlands.
authors.forename: Marijn P A
authors.initials: MP
authors.lastname: Sanders
authors.forename: Luc
authors.initials: L
authors.lastname: Roumen
authors.forename: Eelke
authors.initials: E
authors.lastname: van der Horst
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Jody
authors.initials: J
authors.lastname: van Offenbeek
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Stefan
authors.initials: S
authors.lastname: Verhoeven
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Chow
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Margot W
authors.initials: MW
authors.lastname: Beukers
authors.forename: Ross
authors.initials: R
authors.lastname: McGuire
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Jacob
authors.initials: J
authors.lastname: de Vlieg
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
authors.forename: Jan P G
authors.initials: JP
authors.lastname: Klomp
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry; D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry; D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D015195:Drug Design; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011687:Purines / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D043683:Receptors, Adenosine A2 / Q000737:chemistry* / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D000068677:Sildenafil Citrate; D013269:Stochastic Processes; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D008024:Ligands; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D043683:Receptors, Adenosine A2; D018343:Receptors, Adrenergic, beta-2; D049349:Receptors, Lysosphingolipid; D013450:Sulfones; D000068677:Sildenafil Citrate