Shoda Miyuki, Harada Takeo, Yano Kazuo, Stahura Florence L, Himeno Takeshi, Shiojiri Satoshi, Kogami Yuji, Kouji Hiroyuki, Bajorath Jürgen
Laboratory For Drug Discovery, Research Center, Pharmaceutical R&D Division, Asahi KASEI Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, Japan.
ChemMedChem. 2007 Apr;2(4):515-21. doi: 10.1002/cmdc.200600288.
The binding of lymphocyte function-associated antigen-1 (LFA-1) to its ligand on endothelial cells, intercellular adhesion molecule-1 (ICAM-1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T-cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA-1/ICAM-1 interaction using ligand-based virtual screening (VS), analogue design, and structure-activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of approximately 2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA-1 and ICAM-1.
淋巴细胞功能相关抗原-1（LFA-1）与内皮细胞上的配体细胞间黏附分子-1（ICAM-1）的结合，是炎症早期白细胞迁移过程中的关键步骤，并且还参与T细胞活化。在本文中，我们报告了通过基于配体的虚拟筛选（VS）、类似物设计和构效关系（SAR）分析，鉴定出一系列新型LFA-1/ICAM-1相互作用拮抗剂。在蛋白质结合和细胞黏附试验中对候选化合物进行了评估。从大约250万个数据库化合物库中仅选择25个候选物进行实验评估，就确定了一个初始活性化合物，该化合物可以进一步优化并转化为有效阻断LFA-1与ICAM-1之间相互作用的先导化合物。
