Laboratory of Biological Modeling, National Institutes of Health, Bethesda, MD 20892, USA.
Bioorg Med Chem. 2012 Sep 1;20(17):5254-61. doi: 10.1016/j.bmc.2012.06.044. Epub 2012 Jul 3.
The P2Y(1) receptor (P2Y(1)R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y(1)R ligands and the putative shape and size of the receptor binding pocket, we have identified novel antagonist hits of μM affinity derived from a N,N'-bis-arylurea chemotype. Unlike the vast majority of known P2Y(1)R antagonists, these drug-like compounds do not have a nucleotidic scaffold or highly negatively charged phosphate groups. Hence, our compounds may provide a direction for the development of receptor probes with altered physicochemical properties.
P2Y(1) 受体（P2Y(1)R）是一种 G 蛋白偶联受体，可被细胞外 ADP 自然激活。其刺激是 ADP 诱导血小板聚集的必要条件，因此，其拮抗剂是开发抗血栓药物的理想化合物。在这里，我们通过基于已知 P2Y(1)R 配体的共同特征和假定的受体结合口袋形状和大小的药效团表示的虚拟筛选活动，从 N，N'-双芳基脲化学型中鉴定出具有 μM 亲和力的新型拮抗剂。与绝大多数已知的 P2Y(1)R 拮抗剂不同，这些类药性化合物没有核苷酸支架或高度带负电荷的磷酸基团。因此，我们的化合物可能为开发具有改变的物理化学性质的受体探针提供了方向。
