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

基本信息

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
项目类别：
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

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。 Judith LaLonde，布林莫尔学院：使用基于 ROCS 形状的匹配算法和 gp120 包膜蛋白的分子动力学研究开发新型 HIV 进入抑制剂该计算项目的主要目标是合理设计阻止人类之间相互作用的小分子拮抗剂CD4 细胞表面受体和 HIV-1 的 gp120 包膜蛋白作为治疗 AIDS 的潜在疗法。病毒包膜蛋白 gp120 在与细胞 CD4 受体结合后会发生较大的构象变化，从而随后与趋化因子受体结合并实现病毒-宿主细胞融合 (1)。 NIH PO1 GM 56550 项目团队（细胞进入中 HIV-1 包膜功能的基于结构的拮抗）合成并分析了一系列 NBD 化合物类似物 (2)（图 1，B）。这些化合物与 CD4 竞争与 gp120 的结合，并增强 CD4:gp120 与趋化因子受体 CCR5 的结合。 Schon 等人 (2) 通过 ITC 对 NBD 化合物的热力学性质进行了阐明，表明该化合物类以类似于 CD4 结合的方式诱导 gp120 的结构化。这些化合物在与细胞受体结合之前增强病毒的灭活能力。此类化合物的预测结合模式已通过使用 Glide 的计算对接研究得出 (3, 4)。对一系列具有关键结合位点残基的 NBD 化合物的突变分析表明，某些化合物和突变可增加结合亲和力并增强病毒感染性 (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。在当前的分配过程中，我构建了包含 800 万种药物样化合物的锌集合 (11) 的构象异构体数据库，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 gp120- CD4结合。 AMBER (5) 中实施的分子动力学已用于探索与野生型和 gp120 包膜的各种突变结合的抑制剂 NBD556 的动态波动。分子动力学超过 64 个 gp120 包膜蛋白与各种小分子复合，已完成 100 皮秒轨迹。模拟过程中蛋白质-配体相互作用的定性观察表明哌啶环上四甲基取代的不对称相互作用。野生型和突变型蛋白质-配体复合物的轨迹也可用于使用 Amber 中实施的 MM/PBSA 方法 (9) 来预测结合亲和力。基于 ROCS 的虚拟筛选和 MD 模拟将在下一个分配期（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以及高级技术中心之间分配了 110,000 SU 的资源。当更新可用时，支持 PVM 的实施和算法的优化。利用 PSC 资源的持续、快速周转将进一步加强 HIV 进入抑制剂的基于结构的发现。