Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening
Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening
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在硅片筛选中鉴定有效的新型 α4β1 拮抗剂
DOI：
10.1021/jm020054e
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发表时间：
2002
影响因子：
7.3
通讯作者：
Steven P. Adams
中科院分区：
文献类型：
--
作者：
Juswinder Singh;Herman van Vlijmen;Yusheng Liao;Wen;M. Cornebise;M. Harris;I;A. Gill;Julio H. Cuervo;William M. Abraham;Steven P. Adams
抗原α4β1（极晚期抗原-4，VLA-4）在白色血细胞迁移至炎症部位中起重要作用。它与包括哮喘、多发性硬化和类风湿性关节炎在内的多种疾病的病理学有关。我们描述了一系列有效的α4β1抑制剂，这些抑制剂是使用计算机筛选来替换现有的基于四肽的α4β1抑制剂（1; 4-[N '-（2-甲基苯基）脲基]苯乙酰基-Leu-Asp-Val）的肽区域而发现的，该抑制剂衍生自纤连蛋白。使用1的模型构建检索查询，该模型基于血管细胞粘附分子-1（VCAM-1）的相关整合素结合区的X射线构象。3D检索查询由1的N端帽和羧基侧链组成，因为根据该系列的现有结构-活性数据，已知这些对于与α4β1的高亲和力结合至关重要。计算屏幕从虚拟库中识别出12种试剂...
The antigen α4β1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of α4β1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based α4β1 inhibitor (1; 4-[N‘-(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure−activity data on this series, these were known to be critical for high-affinity binding to α4β1. The computational screen identified 12 reagents from a virtual library of ...