STRUCT.-BASED DESIGN OF INHIB. FOR COMPLEMENT PROTEIN D

基于结构的 INHIB 设计

• 批准号: 3490688
• 负责人: Y SUDHAKARA BABU
• 金额: $ 5万
• 依托单位: BIOCRYST PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-10 至 1992-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3490688
• 关键词: X ray crystallography; active sites; alpha benzopyrone; chemical models; chemical synthesis; complement; complement inhibitors; computer simulation; diisopropylfluorophosphate; drug design /synthesis /production; enzyme complex; enzyme mechanism; enzyme structure; enzyme substrate complex; toluene

DESCRIPTION: (Adapted from the Applicants Abstract). Complement protein Factor D plays an important role in the alternative pathway of the complement system. Inhibitors for Factor D have potential application in the treatment of adult respiratory syndrome (ARDS) and autoimmune diseases such as rheumatoid arthritis. The Phase I aim of this proposal is to determine the three-dimensional structure of Factor D by X-ray crystallographic methods. Diffraction data for native crystals and two potential heavy atom derivatives are in hand. A molecular replacement solution has been obtained using the structure of the homologous serine protease, rat mast cell protease. This model has been refined to an R- value of 0.21, using XPLOR. The investigators plan to improve the initial map by using phase combination (of the molecular replacement and multiple isomorphous replacement phases); build the Factor D model; refine the structure and characterize the active site to understand the mechanism of action. The long term goal in Phase II is to design and synthesize specific inhibitors for Factor D using a structure-based drug design process.

描述：(改编自申请者摘要)。补体蛋白 D因子在血管紧张素转换途径中起着重要作用。 补充制。D因子的抑制剂有潜在的应用前景 成人呼吸综合征和自身免疫性疾病的治疗 比如类风湿性关节炎。这项建议的第一阶段目标是 X-射线测定D因子的三维结构 结晶学方法。天然晶体和两种晶体的衍射数据 潜在的重原子衍生品正在进行中。一种分子替代 使用同源丝氨酸的结构得到了溶液 蛋白酶、大鼠肥大细胞蛋白水解酶。这一型号已被改进为R- 值0.21，使用XploR。调查人员计划改进最初的 使用(分子置换和多重)相组合的映射 同构的替换阶段)；构建因子D模型；细化 对活性中心进行结构和表征以了解其作用机制 行动。第二阶段的长期目标是设计和合成 基于结构的药物设计用于D因子的特异性抑制剂 进程。