Computational Modelling

首席研究员/项目总监（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 人类 CD4 细胞表面受体和 HIV-1 的 gp120 包膜蛋白之间的潜在关系 治疗艾滋病的疗法。在上一个资助期内，综合计划项目已 详细阐述了两种化合物组的抑制机制。 CD4-gp120 的新抑制模式 还发现了肽、微型蛋白质和蛋白质缀合物形式的结合。在 持续期核心A计算模型将详细阐述现有的抑制剂并提供 必要的蛋白质构象设计和建模，以将这些缀合物、肽和小分子转化为 蛋白质转化为生产性抑制剂。核心 A 提出的具体目标是： 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型化合物 2) 生成未配体和 gp120 结合构象的模型，并使用它们来识别和评估 基于结构的抑制剂设计的新靶位点。实现目标 1 需要与 史密斯、柴肯和亨德里克森小组结合实验病毒学评估 索德罗斯基小组，我们进行设计-合成-测试药物发现过程的迭代。会议 目标 2 将需要 Freire 小组、Chaiken 和 Sodroski 小组的实验反馈。未来 gp120 和 Hendrickson 组拮抗剂的共晶将为以下方面提供潜在的新方向 完善对手的设计。建模、综合和反馈之间的动态过程 该计划项目中的实验将导致艾滋病毒拮抗剂的综合有效设计。

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.