TOWARD DEVELOPING NEW ANTIVIRALS AGAINST AVIAN INFLUENZA MEMBRANE GLYCOPROTEINS

致力于开发针对禽流感膜糖蛋白的新型抗病毒药物

• 批准号: 8169360
• 负责人: IAN A WILSON
• 金额: $ 1.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169360
• 关键词: Accounting; Active Sites; Antiviral Agents; Avian Influenza; Binding; Biological Assay; Communities; Complex; Computer Assisted; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Docking; Drug Design; Funding; Goals; Grant; Influenza; Institution; Lead; Ligands; Membrane Glycoproteins; Neuraminidase; Play; Proteins; Research; Research Personnel; Resources; Role; Scheme; Screening procedure; Source; Structure; Techniques; Testing; United States National Institutes of Health; base; computerized tools; design; drug discovery; flexibility; improved; receptor; 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. The influenza membrane glycoproteins, particularly neuraminidase, which is a major antiviral target, are remarkably flexible proteins. Thus it is highly likely that development of new antivirals will depend on our ability to account for and design around this flexibility. This presents a key methodological challenge to the drug discovery community and is one that we are actively pursuing. The overall goals of this collaborative project are to utilize our new computational tool to optimize compounds discovered in virtual screens and then obtain key experimental data in order to improve the current docking approaches for large and highly flexible ligands and receptors. The Wilson lab (TSRI) is a pioneer in determining structures of influenza proteins and is presently testing our first set of newly discovered compounds, which were discovered using the recently developed relaxed complex scheme (RCS) ensemble-based virtual screening technique (presented in (Cheng et al., 2008)), in neuraminidase inhibition assays. Crystallographic data on the precise binding modes of the most promising compounds will also be obtained. These compounds and their binding modes will subsequently be used in the refinement of the project computer-aided drug design (CADD) technique. Based on these results, the McCammon lab will then optimize the compounds using a new AutoDock-based approach to compound optimization that again takes receptor flexibility into account. After optimization, our synthetic collaborators in the Sharpless lab (TSRI) will synthesize the most promising compounds we predict and the Wilson lab will determine their binding modes. Multiple rounds of optimization are envisioned, with the ultimate goal being the development of new compounds that take advantage of the flexibility in the N1 active site region, as compared to other subtypes. The experimental data that we generate will play a critical role in the verification and refinement of the theoretical approach and will aid in the development of new lead compounds that could be developed into antiviral drugs.

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。 流感膜糖蛋白，尤其是神经氨酸酶，是主要抗病毒药靶点，是明显的 柔性蛋白质。因此，新抗病毒药的开发极有可能取决于我们考虑和考虑的能力 设计围绕此灵活性。 这对药物发现社区提出了关键的方法论挑战，这是一个 我们正在积极追求。这个协作项目的总体目标是利用我们的新计算工具来 优化在虚拟屏幕中发现的化合物，然后获得关键的实验数据以改善电流 大型且高度柔韧的配体和受体的对接方法。 威尔逊实验室（TSRI）是确定流感蛋白结构的先驱，目前正在测试我们的第一组 新发现的化合物是使用最近开发的松弛复合方案（RCS）发现的 基于合奏的虚拟筛选技术（在（Cheng等，2008）中，在神经氨酸酶抑制测定中。 还将获得有关最有前途化合物的精确结合模式的晶体学数据。这些 化合物及其约束模式随后将用于计算机辅助药物的细化 设计（CADD）技术。基于这些结果，麦卡蒙实验室将使用新化合物优化化合物 基于自动库克的复合优化方法，该方法再次考虑了受体灵活性。优化后， 我们在Sharpless Lab（TSRI）中的合成合作者将综合我们预测的最有希望的化合物和 威尔逊实验室将确定其结合模式。设想了多轮优化，最终目标是 作为利用N1活动站点区域灵活性的新化合物的开发， 与其他亚型相比。 我们生成的实验数据将在验证中起关键作用， 理论方法的完善，并将有助于开发可以开发的新铅化合物 进入抗病毒药物。