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: 8364292
• 负责人: JUDITH LALONDE
• 金额: $ 0.2万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364292
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Algorithms; Binding; Binding Sites; Biological Assay; Biomedical Research; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; Calorimetry; Cell Surface Receptors; Cell fusion; Cells; Collection; Computer software; Data; Databases; Development; Docking; Eligibility Determination; Funding; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV-1; High Performance Computing; Human; Methods; Mutation; National Center for Research Resources; Pharmaceutical Preparations; Principal Investigator; Property; Proteins; Research; Research Infrastructure; Resources; Screening procedure; Series; Shapes; Source; Structure; Testing; Therapeutic; Thermodynamics; Titrations; United States National Institutes of Health; Update; Viral; Virus; Zinc; analog; base; chemokine receptor; college; conformer; cost; design; molecular dynamics; mutant; novel; process optimization; receptor; small molecule; virtual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Judith LaLonde, Bryn Mawr College: Development of Novel HIV Entry Inhibitors Using the ROCS Shaped Based Matching Algorithm 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). 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 isothermal titration calorimetry by Schon et al (2) indicates that this compound class induces the structuring of gp120 in a manner similar to CD4 binding. These compounds enhance and 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), (Figure 1). 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 (7). This mutational data provides information of key protein interactions responsible for the agonistic properties of the compounds. Over the course of the current allocation the conformer data base of the Zinc collection (8) of 8 million drug-like compounds was used with ROCS (9-11) shaped-based virtual screening methods. This screening protocol was used to identify, synthesize and test over 100 new small molecule analogues of HIV gp120-CD4 binding (12). Over twenty of these are promising new analogues for further optimization. The ROCS screening protocol will continue to be used in the optimization process under the requested renewal period (4-1-11 to 3-31-12). A resource of 90,000 SU on Warhol at the Pittsburgh Super Computing Center as well as Advanced Technical Support for software and PVM support when updates are available is requested. Continued, rapid, virtual screening using PSC resources will further promote the discovery of HIV entry inhibitors.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 Judith LaLonde，布林莫尔学院：使用基于 ROCS 形状的匹配算法开发新型 HIV 进入抑制剂 该计算项目的主要目标是合理设计小分子拮抗剂，阻断人类 CD4 细胞表面受体与 HIV-1 gp120 包膜蛋白之间的相互作用，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）。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) 通过等温滴定量热法阐明了 NBD 化合物的热力学性质，表明此类化合物以类似于 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并使病毒失活。此类化合物的预测结合模式已通过使用 Glide (3, 4) 的计算对接研究得出（图 1）。对具有关键结合位点残基的一系列 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 (7)。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。在当前分配过程中，800 万种药物样化合物的锌集合 (8) 的构象异构体数据库与基于 ROCS (9-11) 形状的虚拟筛选方法一起使用。该筛选方案用于鉴定、合成和测试 100 多种新的 HIV gp120-CD4 结合小分子类似物 (12)。其中二十多个是有望进一步优化的新类似物。 ROCS 筛选协议将在请求的续订期（2011 年 4 月 1 日至 2012 年 3 月 31 日）内继续用于优化过程。匹兹堡超级计算中心的 Warhol 资源为 90,000 SU，并要求在有更新时提供软件高级技术支持和 PVM 支持。利用 PSC 资源进行持续、快速、虚拟的筛查将进一步促进 HIV 进入抑制剂的发现。