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）是抗病毒药物中心不可或缺的组成部分 ＆大流行的准备（CAMPP）及其作用是支持生物物理表征，结构 确定，验证，配体筛查和配体优化可行的药物发现靶标 广告系列。核E将表达和纯化选定的靶蛋白并确定高分辨率3D结构 具有命中化合物的靶标，以帮助目标验证并告知铅优化和结构引导 药物设计与项目和核心合作。同时筛选的两种两种方便的方法 X射线晶体学和单个颗粒电子显微镜的纯化蛋白质将最大程度地提高成功。这 分子结构将在硅配体筛选中启用，并发展分子问题以进行优化 细胞测定中的目标表征，作为SAR分析的结构基础。核心E将有效 与其他项目和核心紧密联系，以识别和优先考虑适合的候选目标 结构确定和随后的基于结构的药物设计和优化。我们还将在结构上 并在计算上验证了高通量屏幕的命中分子，并与高通量一起工作 筛选核心A（HTS）药物化学核心B（MCC），执行委员会和科学委员会 咨询委员会开发承诺将小分子击中铅化合物，并最终临床 候选人。现有的核心E和最先进的设备/技术的现有高水平的专业知识 TSRI将对靶蛋白进行快速的“基因结构”研究。核心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测定高通量结构的领导者（冷冻 EM），在计算机建模中，击中基于结构的优化。为 TSRI的高通量结构生物学在NIH NIH蛋白结构计划（PSI）计划（PSI）计划 结构基因组学大大增强了核心E求解靶蛋白结构以验证的能力 潜在的药物靶标，增强药物发现运动的吞吐量和有效性，并做出贡献 有价值的实验数据，分析和问题。