Computational Modelling

首席调查员/项目主任(最后、第一、中间)：Chaiken，Irwin M./LaLonde，Judith M. 描述：。 该项目的主要目标是合理设计阻断相互作用的小分子拮抗剂。 人CD4细胞表面受体与HIV-1 gp120包膜蛋白之间的相互作用 治疗艾滋病的治疗学。在前一个赠款期间，综合方案项目有 阐述了两种复配物的缓蚀机理。抑制CD_4-gp120的新模式 还发现了以多肽、小蛋白和蛋白质结合物的形式结合。在 持续期间核心A计算模型将详细说明现有的缓蚀剂并提供 对蛋白质构象进行必要的设计和建模，以转化这些偶联物、多肽和迷你... 将蛋白质转化为高效的抑制剂。核心A的拟议具体目标是：1)使用计算方法 开发竞争性Phe43模拟化合物和变构抑制剂的新化合物和 2)生成未连接构象和gp120结合构象的模型，并使用这些模型来识别和评估 基于结构的缓蚀剂设计的新靶点。实现目标1需要与以下人员密切互动 史密斯、柴肯和亨德里克森研究小组与来自 当我们进行设计-合成-测试药物发现过程的迭代时，Sodroski团队。会议 目标2将要求Freire小组、Chaiken小组和Sodroski小组提供实验反馈。未来 Gp120和来自Hendrickson基团的拮抗剂的共晶将提供潜在的新方向 完善对手的设计。建模、综合和反馈的动态过程 该计划项目中的实验将导致一种完整有效的HIV拮抗剂的设计。

Principal Investigator/Program Director (Last, First, Middle): Chaiken, Irwin M. / LaLonde, Judith M. DESCRIPTION:. The key objective of this project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell surface receptor and the gp120 envelope protein of HIV-1 as potential therapeutics for the treatment of AIDS. In the previous grant period the integrated program project has elaborated the mechanism of inhibition of two compound sets. Novel modes of inhibition of CD4-gp120 binding have also been discovered in the form of peptide, mini-[roteins and protein conjugates. In the continuation period Core A computational modeling will elaborate existing inhibitors and provide the necessary designs and modeling of protein conformations to convert these conjugates, peptides and mini- proteins into productive inhibitors. The proposed specific aims of Core A are: 1) Use computational methods to develop novel compounds of competitive Phe43 mimetic compounds and allosteric inhibitors and 2) Generate models of unliganded and gp120 bound conformations, and use these to identify and evaluate novel target sites for structure based inhibitor design. Meeting objective 1 will require close interaction with the Smith, Chaiken and Hendrickson groups in conjunction with experimental virology assessments from the Sodroski group as we carry out iterations of the design-synthesize-test drug discovery process. Meeting objective 2 will require experimental feedback from the Freire group, Chaiken and Sodroski groups. Future co-crystals of gp120 and antagonists from the Hendrickson group will provide potential new directions for refining the antagonist designs. The dynamic process of feedback between modeling, synthesis and experiment in the program project will lead to an integrated and effective design of an HIV antagonist.