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。 驱动蛋白的成员 蛋白质超家族负责重要功能，例如 囊泡运输，染色体分离。 驱动蛋白结合并 水解 ATP，同时附着在微管（相当刚性的聚合物）上 构成细胞细胞骨架的蛋白质。 联轴器 产生定向力和运动的化学能是其中之一 生物学的基本过程。 这种化学机械 在详细的上下文中耦合仍然不被理解 两个驱动蛋白家族成员的分子结构描述：人类 驱动蛋白和 ncd，一种沿相反方向移动的相关马达 沿着微管。 理解驱动蛋白功能的方法 依赖于测量现场定向后改变的运动功能 诱变。 我理解运动功能的方法是 计算各种小有机物之间的结合相互作用 分子和驱动蛋白，目标是找到一种化合物来抑制 或以其他方式在结合的影响下改变驱动蛋白的功能 分子。 我正在使用 UCSF Dock 来筛选可用的数据库 化学物质，并测试一系列预计会结合的化合物。 这 选择取决于计算机图形实验室的设施 用计算机图形在三维空间中查看结合的分子。 迄今为止购买并测试的 90 种左右化合物中，大约有 24 种 这些是驱动蛋白 ATP 酶的亚毫摩尔抑制剂。 更远 需要计算和交互式分子图形 辨别结合模式并发现相似但可能更活跃 化合物。 最后，发现抑制驱动蛋白的化合物可能证明 对于进一步研究细胞过程和疾病状态很有用。