SMALL MOLECULE INHIBITORS TO KINESIN ATPASE ACTIVITY: DRUG DESIGN

激动素是细胞的一种运动蛋白。Kinesin的成员 蛋白质超家族负责重要功能，如 维管运输，染色体分离。动蛋白结合和 水解三磷酸腺苷，同时连接到微管，相当坚硬的聚合物 组成细胞骨架的蛋白质。联结 产生定向力和运动的化学能是其中之一 生物学中的基本过程。这种化学机械 耦合仍然没有在详细的上下文中理解 两个动蛋白家族成员的分子结构描述：人 Kinesin和NCD，一种相反方向移动的相关马达 沿着微管。了解激动素功能的方法 依靠现场定向后对改变的运动功能进行测量 诱变。我理解Kinesing功能的方法是 计算各种有机小分子之间的结合作用 分子和激动素，目的是找到一种化合物来抑制 或在结合的影响下改变动蛋白的功能 分子。我正在使用加州大学旧金山分校的Dock来筛选可用数据库 化学物质，并测试一系列预计会结合的化合物。这 选择依赖于计算机图形实验室的设施 用计算机图形学观察结合分子的三维结构。 到目前为止，在购买和测试的大约90种化合物中，约有24种 这些都是肌动蛋白ATPase的亚毫米级抑制剂。进一步 将需要计算和交互分子图形来 辨别绑定模式，找到相似但可能更活跃的绑定模式 化合物。最后，发现的抑制激动素的化合物可能会证明 对进一步研究细胞过程和疾病状态很有用。

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.