SMALL MOLECULE INHIBITORS TO KINESIN ATPASE ACTIVITY: DRUG DESIGN

驱动蛋白是细胞的运动蛋白。 驱动蛋白成员 蛋白质超家族负责重要功能， 导管运输，染色体分离。 驱动蛋白结合， 水解ATP，同时连接到微管，相当刚性的聚合物 构成细胞骨架的蛋白质。 耦合 产生定向力和运动的化学能是 生物学的基本过程。 这种化学机械 在详细描述的上下文中仍然不理解耦合， 描述了两个驱动蛋白家族成员的分子结构：人类 驱动蛋白和NCD，一种向相反方向运动的相关马达 沿着微管。 理解驱动蛋白功能的方法 依赖于测量定点定向后改变的运动功能， 诱变 我理解驱动功能的方法是 计算各种小的有机物之间的结合相互作用 分子和驱动蛋白，目的是找到一种化合物， 或者在结合的影响下改变驱动蛋白的功能 分子。 我正在用UCSF Dock筛选一个数据库 化学品，并测试预测结合的化合物的选择。 这 选择依赖于计算机图形实验室的设施 用计算机图形学三维地观察结合的分子。 到目前为止，在购买和测试的大约90种化合物中， 这些是驱动蛋白ATP酶的亚毫摩尔抑制剂。 进一步 需要计算和交互式分子图形， 辨别结合的模式，并找到类似的，但可能更活跃， 化合物. 最后，抑制驱动蛋白的化合物可能证明 可用于进一步研究细胞过程和疾病状态。

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.