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.