COMPUTATIONAL

计算型

• 批准号: 8740493
• 负责人: JUDITH LALONDE
• 金额: $ 10.18万
• 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/8740493
• 关键词: Affinity; Algorithms; Binding; Binding Sites; Cells; Chemistry; Collaborations; Crystallography; Development; Docking; Elements; Goals; Grant; HIV Envelope Protein gp120; HIV-1; Homology Modeling; Infection; Ligands; Link; Mediating; Molecular; Peptide antibodies; Peptides; Proteins; Structure; Testing; Thermodynamics; Triazoles; V3 Loop; Validation; Viral; base; chemokine receptor; conformational conversion; design; gp-120 Antigen; inhibitor/antagonist; lead series; mimetics; monomer; novel; peptidomimetics; programs; receptor; screening; simulation; single-molecule FRET; small molecule; success; virology; virtual

Core A Project Summary: The Principal Aim of Core A will be to support the Overarching Goal of this Program Project to identify small molecule and peptide Env gp120 inhibitors, defining their structural mechanisms of action by exploiting structure-mechanism correlations as a guide to optimize antagonist function. To this end, Core A will focus on the recent significant progress made by the Program Project in the development of small molecule and peptidomimetic viral entry antagonists, in conjunction with the emerging structural information of both gpl20 monomer and the Env trimer. We will focus on three Env interfaces that mediate HIV-1 infection. These are: (A) the highly conserved CD4-gp120 binding site; (B) the chemokine receptor-gp120 V3-loop interface; and (C) the gp41-interacfing element of gpl20. During the recent grant period Core A successfully guided cycles of design, synthesis and structure determination for gp 120 antagonists. Building on this success, we will continue to integrate with Crystallography (Hendrickson and Kwong), Virology (Sodroski), Peptide and Mini-proteins (Chaiken), Small Molecule Synthesis (Smith), Thermodynamics (Freire), and Single Molecule FRET (Mothes and Blanchard). Antagonists (peptides, small molecules and fragments) discovered and validated by these groups, will in turn be optimized computationally by Core A, and in collaboration with the Synthetic (Smith) and Peptide/Peptidomimetic Projects (Chaiken) advance novel small molecules and peptides for virological testing and validation (Sodroski).

核心A项目摘要：核心A的主要目的是支持本计划项目的总体目标，即鉴定小分子和肽Env gp 120抑制剂，通过利用结构-机制相关性作为优化拮抗剂功能的指导，确定其结构作用机制。为此，核心A将重点介绍该计划项目最近在开发小分子和拟肽病毒进入拮抗剂方面取得的重大进展，以及gpl 20单体和Env三聚体的新结构信息。我们将集中在三个介导HIV-1感染的Env接口。这些是：（A）高度保守的CD 4-gp 120结合位点;（B）趋化因子受体-gp 120 V3-环界面;和（C）gp 120的gp 41-相互作用元件。在最近的资助期间，核心A成功地指导了gp 120拮抗剂的设计、合成和结构测定。在此成功的基础上，我们将继续整合晶体学（Hendrickson和Kwong），病毒学（Sodroski），肽和迷你蛋白质（Chaiken），小分子合成（Smith），热力学（Freire）和单分子FRET（Mothes和Blanchard）。由这些小组发现和验证的拮抗剂（肽，小分子和片段）将由核心A进行计算优化，并与合成（Smith）和肽/肽模拟物项目（Chaiken）合作，推进用于病毒学测试和验证的新型小分子和肽（Sodroski）。