title: Function-specific virtual screening for GPCR ligands using a combined scoring method.
abstract: The ability of scoring functions to correctly select and rank docking poses of small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe a virtual screening method that combines an energy-based docking scoring function with a molecular interaction fingerprint (IFP) to identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. The consensus scoring method is prospectively evaluated by: 1) the discovery of chemically novel, fragment-like, high affinity histamine H1 receptor (H1R) antagonists/inverse agonists, 2) the selective structure-based identification of ß2-adrenoceptor (ß2R) agonists, and 3) the experimental validation and comparison of the combined and individual scoring approaches. Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H1R and ß2R ligands and the selection of an optimal ß-adrenoceptor crystal structure for the discrimination between ß2R agonists and antagonists. The consensus approach resulted in the experimental validation of 53% of the ß2R and 73% of the H1R virtual screening hits with up to nanomolar affinities and potencies. The selective identification of ß2R agonists shows the possibilities of structure-based prediction of GPCR ligand function by integrating protein-ligand binding mode information.
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: McNaught-Flores
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
mesh_terms: D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057809:HEK293 Cells; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D008024:Ligands; D011943:Receptors, Adrenergic, beta; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D011994:Recombinant Proteins