LIGAND DOCKING SIMULATIONS ON CHORISMATE MUTASES

合理的药物设计取决于对药物的 潜在药物和其他分子的三维形状 参与疾病进程。 不幸的是，没有显微镜 能够提供生物学意义的直接图像， 分子。 然而，通过使用“观察”这种分子是可能的。 X射线晶体学技术 传统的直接方法 技术允许晶体学家数学重建 三维结构的分子负责一个给定的 衍射图案，条件是分子含有不超过 大约100个原子。 不幸的是，大型建筑，包括 在生物体中与药物相互作用的蛋白质分子， 传统上是由劳动密集型方法确定的 需要化学修饰和测量多个 衍射图 事实上，不存在普遍适用的方法 对于含有100-500个原子的分子， 称为摇-烘法（米勒等人，1993年; Weeks，DeTitta， Hauptman，Thuman &米勒，1994）。 过去一年 我们使用IBM SP来解决（以前已知的）1000多个 原子结构，溶菌酶，与我们的SnB（摇烤）程序。 突破1000个原子的屏障是直接核聚变的一个里程碑。 方法研究 我们最近创建了一个并行版本的 SnB 2.0的预发布，这是我们程序的最新版本， 目前正在IBM SP上进行测试。我们希望使用 机器试图解决一个未知的，1600原子结构，由 1997年底。 如果有足够的资源，我们希望能够找到一个解决办法， 在几个月内到手。

Rational drug design depends on having knowledge of the three-dimensional shapes of potential drugs and other molecules involved in disease processes. Unfortunately, no microscope is capable of providing direct images of biologically significant molecules. However, it is possible to "see" such molecules by using the techniques of X-ray crystallography. Traditional direct methods techniques permit crystallographers to mathematically reconstruct the three-dimensional structure of the molecules responsible for a given diffraction pattern provided that the molecules contain no more than approximately 100 atoms. Unfortunately, larger structures, including protein molecules that interact with drugs in living organisms, have traditionally been determined by more labor-intensive methods requiring chemical modification and the measurement of multiple diffraction patterns. In fact, no generally applicable method existed at all for molecules containing 100-500 atoms until a new procedure known as Shake-and-Bake (Miller, et al., 1993; Weeks, DeTitta, Hauptman, Thuman & Miller, 1994) was created. During this past year we have used the IBM SP in order to solve a (previously known) 1000+ atom structure, Lysozyme, with our SnB (Shake-and-Bake) program. Breaking the 1000-atom barrier represented a milestone in direct methods research. We have recently created a parallel version of a pre-release of SnB 2.0, the latest version of our program, which is currently being tested on the IBM SP. We expect to be using this machine to attempt to solve an unknown, 1600-atom structure, by the end of 1997. Given enough resources, we hope that a solution will be at hand within several months.