MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

计算机分子建模和药物设计

• 批准号: 3774558
• 负责人: G W MILNE
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774558
• 关键词: X ray crystallography; chemical models; chemical registry /resource; chemical structure function; computer simulation; drug design /synthesis /production; drug receptors; enzyme structure; model design /development; protein kinase C; protein tyrosine kinase

A broad-based program of analysis and modeling of three-dimensional structures and their use in drug design is in progress. This effort includes pharmacophore identification and analysis, 3D searching of the NCI database and modeling of the active sites in proteins. Modeling Studies Molecular models of structures of interest as chemotherapeutic agents are produced routinely using a variety of computer programs and the models produced have been compared to x-ray structures. Models have been generated of the active sites of various proteins and the mechanism of binding of substrates to these active sites is being studied. Protein Kinase C The pharmacophore of protein kinase C has been characterized in detail, and by searching the NCI 3D database, numerous new PKC activators have been discovered. The model is also used to refine the structures of known binders and so increase their affinity for the enzyme. Tyrosine Protein Kinase The SH2 binding site in several PTK proteins has been characterized and the definition of the putative pharmacophore has been completed. This has enabled searching of the 3D database for peptide and peptidomimetic compounds that can bind to this site and such searches are being carried out. Three-Dimensional Database Conversion of the NCI Database from 2D to 3D has been completed using both the CONCORD and Chem-X programs. A copy of the Chem-X database has been installed on both the DTP VAX and LMC workstations. The Chem-X search programs are running on these workstations and searches can now be done locally.

一种通用的三维有限元分析建模程序 结构及其在药物设计中的使用正在进行中。这一努力 包括药效团识别和分析、3D搜索 NCI数据库和蛋白质中活性位点的建模。 建模研究感兴趣结构的分子模型，如 化疗药物通常是用各种不同的 计算机程序和所产生的模型已经与x射线进行了比较 结构。已经生成了各种类型的活性中心的模型 蛋白质及其底物与这些活性部位的结合机制 正在研究中。 蛋白激酶C是蛋白激酶C的药效团。 特征是详细的，并通过搜索NCI 3D数据库， 发现了新的PKC激活剂。该模型还可用于精化 已知粘结剂的结构，因此增加了它们对 酵素。 酪氨酸蛋白激酶几种PTK蛋白中的SH2结合部位有 以及假定的药效团的定义已经确定 已经完成了。这使得能够在3D数据库中搜索多肽 和可以结合到这个站点和这样的搜索的模拟多肽化合物 正在进行中。 NCI数据库从2D到3D的三维数据库转换 已经使用协和计划和化学-X计划完成。一份副本 的Chem-X数据库已安装在DTP VAX和LMC上 工作站。Chem-X搜索程序在这些设备上运行 现在可以在本地进行工作站和搜索。