title: P2Y1 antagonists: combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring.
abstract: P2Y1 is an ADP-activated G protein-coupled receptor (GPCR). Its antagonists impede platelet aggregation in vivo and are potential antithrombotic agents. Combining ligand and structure-based modeling we generated a consensus model (LIST-CM) correlating antagonist structures with their potencies. We docked 45 antagonists into our rhodopsin-based human P2Y1 homology model and calculated docking scores and free binding energies with the Linear Interaction Energy (LIE) method in continuum-solvent. The resulting alignment was also used to build QSAR based on CoMFA, CoMSIA, and molecular descriptors. To benefit from the strength of each technique and compensate for their limitations, we generated our LIST-CM with a PLS regression based on the predictions of each methodology. A test set featuring untested substituents was synthesized and assayed in inhibition of 2-MeSADP-stimulated PLC activity and in radioligand binding. LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set.
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. stefanoc@mail.nih.gov
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Michihiro
authors.initials: M
authors.lastname: Ohno
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Anny-Odile
authors.initials: AO
authors.lastname: Colson
authors.forename: Dayle
authors.initials: D
authors.lastname: Houston
authors.forename: Savitri
authors.initials: S
authors.lastname: Maddileti
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D058919:Purinergic P2 Receptor Antagonists; D021281:Quantitative Structure-Activity Relationship; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1
chemical_list: C546382:P2RY1 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1