MOLECULAR DYNAMICS STUDIES OF MUTANT HIV GP120 ENVELOP PROTEINS WITH BOUND HIV

突变型 HIV GP120 包膜蛋白与 HIV 结合的分子动力学研究

• 批准号: 8171903
• 负责人: JUDITH LALONDE
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171903
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Algorithms; Amber; Binding; Binding Sites; Biological Assay; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cell fusion; Cells; Collection; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Databases; Development; Docking; Funding; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV-1; Human; Institution; Ligands; Methodology; Methods; Mutation; Pharmaceutical Preparations; Property; Proteins; Research; Research Personnel; Resources; Screening procedure; Series; Shapes; Source; Structure; Therapeutic; Thermodynamics; United States National Institutes of Health; Update; Viral; Virus; Zinc; analog; base; chemokine receptor; college; conformer; design; inhibitor/antagonist; molecular dynamics; mutant; novel; protein complex; receptor; simulation; small molecule; virtual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Judith LaLonde, Bryn Mawr College: Development of Novel HIV Entry Inhibitors Using the ROCS Shaped Based Matching Algorithm and Molecular Dynamics Studies of gp120 Envelop Proteins The key objective of this computational project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell-surface receptor and the gp120 envelop protein of HIV-1 as potential therapeutics for the treatment of AIDS. The viral envelop protein, gp120, undergoes a large conformational change upon binding to the cellular CD4 receptor allowing subsequent binding to the chemokine receptor and viral-host cell fusion (1). The NIH PO1 GM 56550 project team (Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry) has synthesized and assayed a series of NBD compound analogs (2) (Figure 1, B). These compounds compete with CD4 binding to gp120 and enhance binding of CD4:gp120 to the chemokine receptor CCR5. Elucidation of the thermodynamic properties of NBD compounds via ITC by Schon et al (2) indicates that this compound class induces the structuring of gp120 in a manor similar to CD4 binding. These compounds enhance inactive the virus prior to binding to the cellular receptor. A predicted binding mode for this class of compounds has been produced from computational docking studies using Glide (3, 4). Mutational analysis of the series of NBD compounds with key binding site residues has shown certain compounds and mutations increase binding affinity and enhance viral infectivity (10). This mutational data provides information of key protein interactions responsible for the agonistic properties of the compounds. Over the course of the current allocation I have constructed a conformer data base of the Zinc collection (11) of 8 million drug-like compounds and used the ROCS (12-14) shaped based virtual screening methods to develop new active analogues HIV gp120-CD4 binding. Molecular dynamics as implemented in AMBER (5) has been used to explore the dynamic fluctuations of the inhibitor NBD556 bound to wild type and various mutations of the gp120 envelope. Molecular dynamics 100 pico-second trajectories have been completed with over 64 gp120 envelop proteins complexed with various small molecules. A qualitative view of protein-ligand interactions during the simulation indicates an asymmetrical interaction of the tetramethyl substitutions on the piperadine ring. The trajectories of the wild-type and mutant proteins-ligand complexes are also being used to predict binding affinity using the MM/PBSA methodology (9) as implemented in Amber. Both ROCS based virtual screening and MD simulations will be continued during the next allocation period (4-1-10 to 3-31-11) A resource of 110,000 SU split between Warhol and Salk at the Pittsburgh Super Computing Center as well as Advanced Technical Support for implementation of PVM and optimization of algorithms when updates are available. Continued, rapid turn-over using the PSC resources will further enhance the structure-based discovery of HIV entry inhibitors.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 Bryn Mawr学院的朱迪思·拉隆德（Judith Lalonde）：使用基于ROC形状的匹配算法和GP120的分子动力学研究来开发新型HIV进入抑制剂的开发，这些计算项目的关键目标是合理设计的小分子拮抗剂，以阻止人类CD4细胞的相互作用，以阻止人类CD4细胞及GP120的相互作用。艾滋病。病毒包络蛋白GP120在与细胞CD4受体结合时会发生较大的构象变化，从而使随后与趋化因子受体和病毒宿主细胞融合的结合（1）。 NIH PO1 GM 56550项目团队（细胞进入中基于结构的HIV-1信封功能的拮抗作用）已合成并测定了一系列NBD化合物类似物（2）（图1，b）。这些化合物与CD4与GP120结合并增强CD4：GP120与趋化因子受体CCR5的结合。 Schon等人（2）通过ITC阐明NBD化合物的热力学特性表明，该化合物类别在类似于CD4结合的庄园中诱导GP120的结构。这些化合物在与细胞受体结合之前会增强病毒不活跃。使用Glide（3，4），通过计算对接研究产生了这类化合物的预测结合模式。对具有关键结合位点残基的NBD化合物系列的突变分析已显示某些化合物和突变增加了结合亲和力并增强了病毒感染性（10）。该突变数据提供了负责化合物激动特性的关键蛋白质相互作用的信息。在当前分配的过程中，我构建了800万种类似药物的化合物的锌收集（11）的构象象形数据库，并使用了基于ROCS（12-14）形状的虚拟筛选方法来开发新的主动类似物HIV GP120-CD4结合。在琥珀（5）中实现的分子动力学已用于探索与野生型结合的抑制剂NBD556的动态波动和GP120包膜的各种突变。分子动力学100 pico秒轨迹已完成，超过64个GP120包络蛋白与各种小分子复合。在模拟过程中，蛋白质 - 配体相互作用的定性视图表明，四甲基取代在哌啶环上的不对称相互作用。野生型和突变蛋白配体的轨迹也用于使用琥珀中实现的MM/PBSA方法（9）来预测结合亲和力。在下一个分配期（4-1-10到3-31-11）将继续进行基于ROC的虚拟筛选和MD模拟，在匹兹堡超级计算中心的Warhol和Salk之间分配了110,000 SU的资源，以及实施PVM和Algorithms的先进技术支持。使用PSC资源进行持续的快速转换将进一步增强基于结构的HIV进入抑制剂的发现。