Structural and Modeling Core

结构和建模核心

• 批准号: 10514323
• 负责人: IAN A WILSON
• 金额: $ 565.96万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514323
• 关键词: Acrylamides; Antibodies; Biochemical; Biological Assay; Biophysics; Boronic Acids; Cellular Assay; Chemistry; Collaborations; Collection; Complex; Cryoelectron Microscopy; Crystallization; Data; Development; Docking; Drug Design; Drug Targeting; Effectiveness; Electron Microscopy; Equipment; Foundations; Generations; Genes; Goals; Immunoglobulin Fragments; Infrastructure; Lead; Libraries; Ligands; Medicine; Methods; Modeling; Molecular Probes; Molecular Structure; Molecular Weight; Pharmaceutical Chemistry; Polymerase; Positioning Attribute; Post-Translational Protein Processing; Production; Property; Protein Structure Initiative; Proteins; Research; Research Design; Resolution; Role; Sampling; Source; Structural Models; Structure; Synchrotrons; System; Technology; United States National Institutes of Health; Validation; Viral Proteins; Work; X-Ray Crystallography; base; biophysical analysis; biophysical properties; clinical candidate; data acquisition; design; drug discovery; experience; experimental study; high throughput screening; improved; in silico; inhibitor; interest; lead optimization; molecular modeling; new therapeutic target; novel; pandemic preparedness; particle; programs; protein complex; protein structure; screening; small molecule; small molecule libraries; structural biology; structural genomics; success; three dimensional structure; tool; virtual; virtual screening; ward

SUMMARY The Structural and Modeling Core (Core E) is an integral component of the Center for Antiviral Medicines & Pandemic Preparedness (CAMPP) and its role is to support biophysical characterization, structure determination, validation, ligand screening and ligand optimization of viable targets for drug discovery campaigns. Core E will express and purify selected target proteins and determine high-resolution 3D structures of targets with hit compounds to assist target validation and inform on lead optimization and structure-guided drug design in collaboration with the Projects and Cores. A two-pronged approach of simultaneous screening of purified proteins by x-ray crystallography and single particle electron microscopy will maximize success. The molecular structures will enable in silico ligand screening, and development of molecular probes for optimized target characterization in cellular assays that serve as structural foundations for SAR analyses. Core E will work closely with the other Projects and Cores to identify and prioritize candidate targets that are amenable for structure determination and subsequent structure-based drug design and optimization. We will also structurally and computationally validate hit molecules from high-throughput screens and work with the High Throughput Screening Core A (HTS) Medicinal Chemistry Core B (MCC), Executive Committee, and Scientific Advisory Board to develop promising small molecule hits into lead compounds, and ultimately clinical candidates. The existing high level of expertise in Core E and the state-of-the art equipment/technologies at TSRI will enable rapid “gene-to-structure” studies of the target proteins. Core E is led by recognized world leaders in high-throughput structure determination by x-ray crystallography and cryo-electron microscopy (cryo- EM), in silico modeling, hit generation and structure-based optimization. The extensive infrastructure built for high-throughput structural biology at TSRI in the 16-year NIH Protein Structure Initiative (PSI) program in structural genomics substantially augments Core E’s ability to solve structures of target proteins to validate potential drug targets, enhance the throughput and effectiveness of drug discovery campaigns, and contribute valuable experimental data, assays, and probes to CAMPP.

摘要 结构和模型核心(核心E)是抗病毒药物中心不可或缺的组成部分 和大流行防备(CAMPP)，其作用是支持生物物理表征、结构 药物发现活性靶点的确定、验证、配基筛选和配基优化 竞选活动。Core E将表达和纯化选定的目标蛋白，并确定高分辨率的3D结构 具有命中化合物的目标，以帮助目标验证并通知引线优化和结构制导 与项目和核心合作进行药物设计。双管齐下的同步筛查方法 通过X射线结晶学和单粒子电子显微镜对纯化蛋白质的分析将最大限度地取得成功。这个 分子结构将使在硅胶中筛选配体，并开发分子探针进行优化 细胞分析中的目标表征，作为合成孔径雷达分析的结构基础。核心E将正常工作 与其他项目和核心密切合作，以确定并确定符合以下条件的候选目标的优先顺序 结构确定和后续基于结构的药物设计和优化。我们还将在结构上 并通过计算验证来自高通量屏幕的命中分子，并与High Throughut一起工作 筛选核心A(HTS)药物化学核心B(MCC)、执行委员会和科学 顾问委员会将把有前途的小分子His开发成先导化合物，并最终用于临床 候选人。CoreE现有的高水平专业知识和最先进的设备/技术 TSRI将使目标蛋白质的快速“基因-结构”研究成为可能。核心E由公认的世界领导 X射线结晶学和低温电子显微镜高通量结构测定领域的领先者 EM)，在Silico建模、命中生成和基于结构的优化中。广泛的基础设施是为 美国国立卫生研究院蛋白质结构倡议(PSI)16年计划中的高通量结构生物学 结构基因组学大大增强了Core E解决目标蛋白质结构验证的能力 潜在的药物靶点，提高药物发现活动的吞吐量和有效性，并作出贡献 对CAMPP有价值的实验数据、分析和探针。