Structural and Modeling Core

总结 结构和建模核心（核心E）是抗病毒药物中心的一个组成部分 和大流行防范（CAMPP），其作用是支持生物物理表征，结构 用于药物发现的可行靶点的确定、验证、配体筛选和配体优化 竞选核心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 目标与命中化合物，以协助目标验证，并告知铅优化和结构指导 药物设计与项目和核心合作。双管齐下的同步筛查方法 通过X射线晶体学和单粒子电子显微镜对纯化的蛋白质进行分析将最大限度地提高成功率。的 分子结构将能够在计算机上进行配体筛选，并开发用于优化的分子探针。 作为SAR分析的结构基础的细胞测定中的靶向表征。核心E将工作 与其他项目和核心密切合作，确定并优先考虑适合的候选目标 结构测定和随后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筛选的命中分子， 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 顾问委员会将有前途的小分子药物开发成先导化合物，并最终用于临床 候选人现有的高水平的核心E专业知识和最先进的设备/技术， TSRI将使靶蛋白的快速“基因到结构”研究成为可能。Core E由世界公认的 通过X射线晶体学和低温电子显微镜（cryo， EM）、计算机建模、命中生成和基于结构的优化。广泛的基础设施， TSRI的高通量结构生物学在16年的NIH蛋白质结构倡议（PSI）计划中， 结构基因组学大大增强了Core E解决靶蛋白结构的能力， 潜在的药物靶点，提高药物发现活动的吞吐量和有效性， 有价值的实验数据，分析和探针CAMPP。

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.