SMALL MOLECULE INHIBITORS TO KINESIN ATPASE ACTIVITY: DRUG DESIGN

驱动蛋白ATP酶活性的小分子抑制剂：药物设计

• 批准号: 6456789
• 负责人: SETH C HOPKINS
• 金额: $ 27.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456789
• 关键词: bacteria; biological products; biomedical resource; hormones

Kinesin is a motor protein of the cell. Members of the kinesin superfamily of proteins are responsible for vital functions such as vessicle transport, chromosome segregation. Kinesin proteins bind and hydrolyze ATP whilst attached to microtubules, fairly rigid polymers of proteins that make up the cytoskeleton of the cell. The coupling of the chemical energy to produce directed force and movement is one of the fundamental processes in biology. This chemomechanical coupling is still not understood in the context of the detailed molecular structure described for two kinesin family-members: human kinesin and ncd, a related motor that moves in the opposite direction along the microtubules. Methods of understanding kinesin function rely on measuring the altered motor function after site-directed mutagenesis. My approach to understanding kinesing function is to calculate a binding interaction between various small organic molecules and kinesin, with the goal of finding a compound to inhibit or otherwise alter kinesin's function under the influence of the bound molecule. I am using UCSF Dock to screen a database of available chemicals, and test a selection of compounds predicted to bind. This selection relies on the facilities of the Computer Graphics Laboratory to view the bound molecule in three-dimensions with computer graphics. Out of the 90 or so compounds bought and tested so far, about 24 of these are sub-millimolar inhibitors of kinesin ATPase. Further calculations and interactive molecular graphics will be needed to discern the modes of binding and find similar but possibly more active compounds. Finally, compounds found to inhibit kinesin may prove useful for further study in cellular processes and disease states.

驱动蛋白是细胞的运动蛋白。 运动蛋白的成员 蛋白质的超家族负责重要功能 血管运输，染色体分离。 驱动蛋白蛋白结合和 水解ATP时，固定在微管上，相当刚性聚合物 构成细胞细胞骨架的蛋白质。 耦合 产生定向力和运动的化学能是一个 生物学的基本过程。 这种化学力学 在详细的背景下，耦合仍然不理解 针对两个动力蛋白家庭成员描述的分子结构：人类 动力素和NCD，这是一种相关的电动机，朝相反的方向移动 沿着微管。 理解驱动蛋白功能的方法 依靠测量位置后的运动功能改变的运动功能 诱变。 我理解Kinening功能的方法是 计算各种小有机体之间的结合相互作用 分子和运动蛋白，目的是找到抑制的化合物 或否则在绑定的影响下改变动力蛋白的功能 分子。 我正在使用UCSF Dock筛选可用的数据库 化学物质，并测试预测结合的化合物的选择。 这 选择依赖计算机图形实验室的设施 用计算机图形查看三维中的结合分子。 到目前为止，购买和测试的90种左右的化合物中约有24个 这些是驱动蛋白ATPase的亚氨基摩尔抑制剂。 更远 需要计算和交互式分子图形 辨别绑定的模式，并找到相似但可能更活跃的方式 化合物。 最后，发现抑制驱动蛋白的化合物可能证明 可用于在细胞过程和疾病状态中进一步研究。