STRUCTURAL STUDIES OF FIV PROTEASE INHIBITOR COMPLEXES

我们将使用X射线结晶学来研究化合物的分子结构 猫免疫缺陷病毒蛋白水解酶(FIV PR)作为程序的基础 旨在开发基于结构和机理的药物开发工具 设计。对FIV PR分子结构的理解 背景将有助于基于以下内容的艾滋病疗法的发展 抑制HIV-1PR。首先，FIV PR的分子结构将是 根据RSV PR和HIV-1 PR的结构建模得出 是由我们实验室测定的。这样的模型将在 FIV的X射线晶体结构的实验测定 PR，并用于初步的缓蚀剂设计。FIV PR的晶体结构 将被确定，未连接，并以底物为基础的络合物 抑制剂。这些信息将用于第一轮 抑制剂/药物设计。从第一轮设计中挑选出的抑制剂 将用于FIV PR-抑制剂复合体的进一步研究。已选择 PR-抑制剂络合物将被测定到非常高的分辨率 为定量理解酶配体提供依据 互动。缓蚀剂的精细化设计及设计工具的改进 将以这种迭代方式获得的数据为基础。FIV公关 将所获得的结构与RSV PR和 HIV-1公关结构，以得出关于结构的一般推断 这些重要的逆转录病毒酶特性的起源。

We will use X-ray crystallography to study the molecular structure of the Feline Immunodeficiency Virus protease (FIV PR) as the basis for a program aimed at developing the tools for structure and mechanism based drug design. Understanding of the molecular structure of the FIV PR in that context will contribute to the development of AIDS therapeutics based on inhibiting the HIV-1 PR. First, the molecular structure of FIV PR will be worked out by modelling based on the structures of RSV PR and HIV-1 PR determined in our laboratory. Such a model will be useful in experimentally determining the X-ray crystallographic structure of the FIV PR, and for preliminary inhibitor design. The crystal structure of FIV PR will be determined, unliganded and as a complex with substrate-based inhibitors. This information will be used in an initial round of inhibitor/drug design. Inhibitors selected from this first round of design will be used in further studies of the FIV PR-inhibitor complex. Selected PR-inhibitor complexes will be determined to very high resolution to provide the basis for quantitative understanding of enzyme-ligand interactions. Refined inhibitor design and improvement of the design tools will be based on data obtained in this iterative fashion. The FIV PR structures obtained will be compared and contrasted with the RSV PR and HIV-1 PR structures to draw general inferences concerning the structural origins of the properties of these important retroviral enzymes.