LIGAND DOCKING SIMULATIONS ON CHORISMATE MUTASES

分支酸变位酶的配体对接模拟

• 批准号: 6121987
• 负责人: BRUCE GANEM
• 金额: $ 1.8万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6121987
• 关键词: biological products; biomedical resource; computers; structural biology; technology /technique

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.

合理的药物设计取决于对药物的了解 潜在药物和其他分子的三维形状 参与疾病过程。 可惜没有显微镜 能够提供具有生物学意义的直接图像 分子。 然而，可以通过使用“看到”这些分子 X射线晶体学技术。 传统直接法 技术允许晶体学家以数学方式重建 负责给定的分子的三维结构 衍射图案只要分子含有不超过 大约100个原子。 不幸的是，更大的结构，包括 与生物体中的药物相互作用的蛋白质分子， 传统上是通过劳动密集型方法来确定的 需要化学修饰和多重测量 衍射图案。 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，直到出现新程序为止 称为摇动烘烤（Miller 等，1993；Weeks，DeTitta， Hauptman、T human 和 Miller，1994 年）创建。 在过去的这一年里 我们使用 IBM SP 来解决（以前已知的）1000+ 原子结构、溶菌酶，以及我们的 SnB（摇动烘烤）程序。 突破 1000 个原子的障碍是直接化学领域的一个里程碑 方法研究。 我们最近创建了一个并行版本 SnB 2.0 预发布，我们程序的最新版本，即 目前正在 IBM SP 上进行测试。 我们期望使用这个 机器尝试解决未知的 1600 个原子结构 1997 年底。如果有足够的资源，我们希望能够找到解决方案 几个月内就到手了。