Computational Modelling

主要研究者/项目负责人（最后一名、第一名、中间名）：Chaiken，欧文M.作者：LaLonde，Judith M. 描述：. 本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CD 4细胞表面受体和HIV-1的gp 120包膜蛋白之间的相互作用， 用于治疗艾滋病的治疗剂。在上一个资助期内，综合计划项目已 阐述了两种化合物的抑菌机理。抑制CD 4-gp 120的新模式 还发现了肽、小鱼藤蛋白和蛋白质缀合物形式的结合。在 延续期核心A计算建模将详细说明现有的抑制剂，并提供 必要的设计和蛋白质构象的建模，以将这些缀合物、肽和小分子转化为蛋白质。 蛋白质转化为生产性抑制剂。核心A的拟议具体目标是：1）使用计算方法 开发竞争性Phe 43模拟化合物和变构抑制剂的新化合物， 2)生成未配体和gp 120结合构象的模型，并使用这些模型来识别和评估 用于基于结构的抑制剂设计的新靶位点。实现目标1将需要与下列机构密切互动： Smith、Chaiken和Hendrickson小组结合来自 Sodroski小组，因为我们进行设计-合成-测试药物发现过程的迭代。会议 目标2将需要来自弗莱雷小组、柴肯小组和索德罗斯基小组的实验反馈。未来 来自Hendrickson组的gp 120和拮抗剂的共晶体将为 改进拮抗剂的设计建模、综合与建模之间的动态反馈过程 该计划项目的实验将导致一个综合和有效的设计艾滋病毒拮抗剂。

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.