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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Judith LaLonde，Bryn Mawr学院：使用ROCS Shaped Based Matching Algorithm和gp 120 Envelop Proteins的分子动力学研究开发新型HIV进入抑制剂本计算项目的主要目标是合理设计小分子拮抗剂，阻断人类CD 4细胞表面受体与HIV-1的gp 120 Envelop蛋白之间的相互作用，作为治疗艾滋病的潜在疗法。病毒包膜蛋白gp 120在与细胞CD 4受体结合后发生大的构象变化，从而允许随后与趋化因子受体结合和病毒-宿主细胞融合（1）。NIH PO 1 GM 56550项目组（细胞进入中HIV-1包膜功能的基于结构的拮抗作用）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CD 4竞争结合gp 120，并增强CD 4：gp 120与趋化因子受体CCR 5的结合。Schon等人（2）通过ITC对NBD化合物的热力学性质进行的解释表明，该类化合物以类似于CD 4结合的方式诱导gp 120的结构化。这些化合物在与细胞受体结合之前增强病毒的失活。这类化合物的预测结合模式已通过使用Glide的计算对接研究产生（3，4）。具有关键结合位点残基的NBD化合物系列的突变分析显示，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性质的关键蛋白质相互作用的信息。在目前的分配过程中，我构建了800万种药物样化合物的锌集合（11）的构象数据库，并使用基于ROCS（12-14）形状的虚拟筛选方法来开发新的活性类似物HIV gp 120-CD 4结合。AMBER（5）中实施的分子动力学已用于探索与野生型和gp 120包膜的各种突变结合的抑制剂NBD 556的动态波动。分子动力学100皮秒的轨迹已经完成了超过64个gp 120包膜蛋白与各种小分子复合。在模拟过程中的蛋白质-配体相互作用的定性视图表明哌啶环上的四甲基取代的不对称相互作用。野生型和突变蛋白-配体复合物的轨迹也用于使用Amber中实施的MM/PBSA方法（9）预测结合亲和力。基于ROCS的虚拟筛选和MD模拟都将在下一个分配期间（2010年4月1日至2011年3月31日）继续进行。沃霍尔和索尔克在匹兹堡超级计算中心分配了110，000 SU的资源，以及在更新可用时用于PVM实施和算法优化的高级技术支持。使用PSC资源的持续、快速周转将进一步加强基于结构的HIV进入抑制剂的发现。