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
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
J Med Chem. 2007 Jul 12;50(14):3229-41. doi: 10.1021/jm0700971. Epub 2007 Jun 12.
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.
P2Y1是一种由二磷酸腺苷（ADP）激活的G蛋白偶联受体（GPCR）。其拮抗剂可在体内抑制血小板聚集，是潜在的抗血栓形成药物。结合基于配体和结构的建模方法，我们构建了一个将拮抗剂结构与其效价相关联的共识模型（LIST-CM）。我们将45种拮抗剂对接至基于视紫红质的人类P2Y1同源模型中，并采用连续介质溶剂中的线性相互作用能（LIE）方法计算对接分数和自由结合能。所得比对结果还用于基于比较分子场分析（CoMFA）、比较分子相似性指数分析（CoMSIA）和分子描述符构建定量构效关系（QSAR）。为了利用每种技术的优势并弥补其局限性，我们基于每种方法的预测结果，通过偏最小二乘（PLS）回归生成了LIST-CM。合成了一组具有未测试取代基的测试集，并对其抑制2-甲基硫代二磷酸腺苷（2-MeSADP）刺激的磷脂酶C（PLC）活性以及放射性配体结合的能力进行了测定。LIST-CM在预测测试集中75%的化合物效价方面，其内部和外部预测能力均优于任何单一模型。
