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.

概括 结构和建模核心（核心 E）是抗病毒药物中心的组成部分 和流行病防范 (CAMPP) 其作用是支持生物物理特征、结构 药物发现可行靶标的确定、验证、配体筛选和配体优化 Core E 将表达和纯化选定的目标蛋白并确定高分辨率 3D 结构。 具有命中化合物的目标，以协助目标验证并为先导化合物优化和结构指导提供信息 与项目和核心合作进行药物设计同时筛选的双管齐下的方法。 通过 X 射线晶体学和单粒子电子显微镜纯化蛋白质将最大限度地取得成功。 分子结构将使计算机配体筛选成为可能，并开发分子探针以优化 细胞分析中的目标表征可作为 SAR 分析的结构基础。 与其他项目和核心密切合作，确定适合的候选目标并确定其优先顺序 结构确定以及随后的基于结构的药物设计和优化我们还将在结构上进行。 并通过计算验证来自高通量筛选的命中分子并与高通量一起工作 筛选核心 A (HTS) 药物化学核心 B (MCC)、执行委员会和科学 顾问委员会将开发有前景的小分子药物作为先导化合物，并最终进入临床 现有的 Core E 方面的高水平专业知识和最先进的设备/技术。 TSRI 将实现对目标蛋白的快速“基因到结构”研究，Core E 由公认的世界领导。 通过 X 射线晶体学和冷冻电子显微镜（冷冻电子显微镜）进行高通量结构测定的领导者 EM），计算机建模、命中生成和基于结构的优化。 TSRI 在 16 年 NIH 蛋白质结构计划 (PSI) 项目中的高通量结构生物学 结构基因组学大大增强了 Core E 解决目标蛋白结构以进行验证的能力 潜在的药物靶标，提高药物发现活动的通量和有效性，并做出贡献 为 CAMPP 提供有价值的实验数据、分析和探针。