LIGAND DOCKING SIMULATIONS ON CHORISMATE MUTASES

合理的药物设计依赖于对 潜在药物和其他分子的三维形状 参与疾病过程。不幸的是，没有显微镜是 能够提供具有生物学意义的直接图像的 分子。然而，通过使用电子计算机可以“看到”这种分子。 X射线结晶学技术。传统直接法 技术使结晶学家能够在数学上重建 对给定的分子负责的分子的三维结构 如果分子中含有不超过 大约100个原子。不幸的是，更大的结构，包括 在活体中与药物相互作用的蛋白质分子 传统上是通过更劳动密集型的方法确定的 需要化学修饰和测量多个 衍射图。事实上，还没有普遍适用的方法。 对于包含100-500个原子的分子，直到一个新的程序 被称为摇动和烘焙(Miller等人，1993；Week，Deitta， Hauptman，THuman&Miller，1994)被创建。在过去的一年里 我们使用IBM SP来解决(以前已知的)1000 原子结构，溶菌酶，与我们的SNB(摇动烘焙)程序。 突破1000个原子的障碍代表着直接 方法研究方法。我们最近创建了一个并行版本的 我们程序的最新版本SNB 2.0的预发布，它是 目前正在IBM SP上进行测试。我们预计将使用这一技术 这台机器试图解决一个未知的，1600个原子结构，由 1997年底。如果有足够的资源，我们希望解决方案将是 在几个月内就可以完成。

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.