Computational Modelling

计算建模

• 批准号: 7914099
• 负责人: JUDITH LALONDE
• 金额: $ 12.92万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7914099
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Agonist; Binding; Binding Sites; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Chemistry; Computer Simulation; Computing Methodologies; Crystallography; Data; Epitopes; Feedback; Future; Grant; HIV; HIV 1 Envelope Protein gp120; HIV Envelope Protein gp120; HIV-1; Homology Modeling; Human; Lead; Maps; Modeling; Modification; Molecular; Molecular Conformation; Peptides; Principal Investigator; Process; Property; Protein Conformation; Proteins; Research Personnel; Screening procedure; Series; Site; Structure; Structure-Activity Relationship; Testing; Therapeutic; Thermodynamics; Variant; Viral; analog; base; design; drug discovery; flexibility; follow-up; inhibitor/antagonist; meetings; mimetics; model design; molecular dynamics; novel; piperidine; programs; receptor; receptor binding; research study; simian immunodeficiency virus gp120; small molecule; virology; water channel

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.

首席调查员 /计划主管（最后，第一，中间）：Chaiken，Irwin M. / Lalonde，Judith M. 描述：。 该项目的关键目的是合理设计阻断相互作用的小分子拮抗剂 在人CD4细胞表面受体和HIV-1的GP120包膜蛋白之间 治疗艾滋病的治疗剂。在上一个赠款期间，集成计划项目已有 阐述了抑制两个化合物集的机制。 CD4-GP120抑制的新型模式 结合也已经以肽，微型（死记硬背和蛋白质结合物的形式）发现。在 延续期核心计算建模将详细说明现有抑制剂，并提供 蛋白质构象的必要设计和建模，以转化这些结合物，肽和微型 蛋白质成生产抑制剂。核心A的拟议特定目的是：1）使用计算方法 开发具有竞争性Phe43模拟化合物和变构抑制剂的新型化合物 2）生成非配体和GP120结合构象的模型，并使用这些模型来识别和评估 基于结构的抑制剂设计的新型目标位点。达到目标1将需要与 Smith，Chaiken和Hendrickson组以及实验性病毒学评估 Sodroski组在我们进行设计合成的测试药物发现过程中进行迭代。会议 目标2将需要Freire组，Chaiken和Sodroski组的实验反馈。未来 GP120的共结晶和亨德里克森集团的拮抗剂将为潜在的新方向提供 完善对手设计。建模，合成和 计划项目的实验将导致HIV拮抗剂的综合有效设计。