STRUCTURAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

这项提案将侧重于使用结构生物学来帮助 能以特定方式进行干预的药物的发展 使用人类免疫缺陷病毒(HIV)的蛋白质产品 基因组。因为HIV是牵涉到 获得性免疫缺陷综合征(AIDS)，希望 这些药物将治愈或至少阻止艾滋病的症状。 在极其紧迫的健康优先事项中寻找艾滋病的治疗方法 为了这个世界。然而，可以预见的是， 在这个以艾滋病为目标的项目中制定的方法可以 开发其他抗病毒药物的基础 这将不可避免地在未来演变为人类的斑块。 针对几种HIV蛋白的抑制剂将被开发： 逆转录酶、蛋白酶、整合酶和 逆转录酶的核糖核酸酶H活性。 生产病毒蛋白的重组方法将是 发展起来的。这些蛋白以及获得的病毒蛋白 从外部来源，适当地，将被高度提纯， 结晶并经受X射线衍射(或核磁共振) 分析。新出现的结构将使用以下方法建模 计算机图形学，以及潜在的抑制剂将反过来 用分子力学、量子力学、量子力学来模拟结构 机械学和人工智能。 将合成候选抑制剂，并用酶进行测试 系统，有时与酶共结晶 进一步的结构分析。更强大和更强大的想法 然后，应该会出现选择性的抑制剂。现场定向- 突变将被用来改进关于哪些基团在 这些酶参与了抑制过程。

This proposal will focus on the use of structural biology to aid in the development of drugs that can interfere in a specific manner with protein products of the human immunodeficiency virus (HIV) genome. Since HIV is the etiological agent implicated in Acquired Immunodeficiency Syndrome (AIDS), it is hoped that these drugs will cure or at least arrest the symptoms of AIDS. Finding a cure for AIDS in an extremely urgent health priority for the world. However, it can be anticipated that the methodologies developed in this AIDS-targeted project could lay the foundations for the development of other anti-viral agents that inevitably will evolve in the future to plaque mankind. Inhibitors will be developed toward several HIV proteins: the reverse transcriptase, the protease, the integrase and the ribonuclease H activity of the reverse transcriptase. Recombinant methods for viral protein production will be developed. These proteins, as well as viral proteins obtained from external sources, as appropriate, will be highly purified, crystallized and subjected to X-ray diffraction (or NMR) analysis. The emerging structures will be modeled using computer graphics, and potential inhibitors will in turn be modeled into the structures using molecular mechanics, quantum mechanics and artificial intelligence. Candidate inhibitors will be synthesized, tested with enzyme systems, and sometimes co-crystallized with the enzyme for further structural analysis. Ideas for even more potent and selective inhibitors should then emerge. Site-directed- mutagenesis will be used to refine notions about which groups on the enzyme are involved in the inhibitor process.