Costanzi, Stefano Tikhonova, Irina G. Ohno, Michihiro Roh, Eun Joo Joshi, Bhalchandra V. Colson, Anny-Odile Houston, Dayle Maddileti, Savitri Harden, T. Kendall Jacobson, Kenneth A. 2024-01-21T00:35:32Z 2024-01-21T00:35:32Z 2021-08-31 2007-07-12 0022-2623 https://pubs.kist.re.kr/handle/201004/134270 P2Y(1) 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 P2Y(1) 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. English AMER CHEMICAL SOC NUCLEOTIDE RECEPTORS PLATELET-AGGREGATION POTENT ANTAGONISTS BINDING-AFFINITY PHOSPHOLIPASE-C RATIONAL DESIGN ANALOGS AGONISTS NUCLEOSIDES DERIVATIVES P2Y(1) antagonists: Combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring Article 10.1021/jm0700971 1 JOURNAL OF MEDICINAL CHEMISTRY, v.50, no.14, pp.3229 - 3241 JOURNAL OF MEDICINAL CHEMISTRY 50 14 3229 3241 scie scopus 000247760400010 Chemistry, Medicinal Pharmacology & Pharmacy Article NUCLEOTIDE RECEPTORS PLATELET-AGGREGATION POTENT ANTAGONISTS BINDING-AFFINITY PHOSPHOLIPASE-C RATIONAL DESIGN ANALOGS AGONISTS NUCLEOSIDES DERIVATIVES P2Y1 receptor QSAR GPCR