STRUCTURAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

该提案将重点关注结构生物学的使用，以帮助 药物的开发可以以特定的方式干扰 人类免疫缺陷病毒（HIV）的蛋白质产物 基因组 由于艾滋病毒是与艾滋病有关的病原体， 获得性免疫缺陷综合症（艾滋病），希望 这些药物将治愈或至少抑制艾滋病的症状。 在极其紧迫的卫生优先事项中找到艾滋病的治愈方法 为世界 然而，可以预见， 在这个以艾滋病为目标的项目中开发的方法， 为其他抗病毒药物的开发奠定了基础 在未来不可避免地会进化成人类的斑块。 将针对几种HIV蛋白开发抑制剂： 逆转录酶、蛋白酶、整合酶和 逆转录酶的核糖核酸酶H活性。 用于病毒蛋白生产的重组方法将是 开发 这些蛋白质，以及病毒蛋白质获得 从外部来源，适当的话，将被高度纯化， 结晶并进行X射线衍射（或NMR） 分析. 新出现的结构将使用 计算机图形，和潜在的抑制剂将反过来是 利用分子力学、量子力学 机械和人工智能。 候选抑制剂将被合成，用酶测试 系统，有时与酶共结晶， 进一步结构分析。 更有效的想法， 选择性抑制剂应该出现。 现场指导- 诱变将被用来完善概念，哪些群体对 酶参与抑制剂过程。

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.