Abstract Shared Resource 04: Drug Discovery & Structural Biology (DDSB-SR) The Drug Discovery and Structural Biology Shared Resource (DDSB-SR) collaborates with COHCCC Members to validate, develop, optimize, and translate novel therapeutics. To accomplish this, the DDSB-SR provides a comprehensive range of drug discovery services spanning computational modeling; high throughput screening (HTS); synthetic organic chemistry/medicinal chemistry, peptide synthesis, modified DNA/RNA oligonucleotide synthesis, and expertise in protein structure and biophysical methods. These highly specialized services provide COHCCC Members with a cohesive and comprehensive platform to rapidly and successfully translate their scientific discoveries to meaningful clinical outcomes. Specific Aims of the DDSB-SR: Aim 1. High throughput small molecule screening and fragment-based screening. Aim 2. Medicinal chemistry and solid phase synthesis of custom peptides & oligonucleotides of high structural complexity. Aim 3. Protein production and purification, molecular interaction analysis, and diffraction studies. Aim 4. Cutting-edge computational methods to support the design new therapeutic agents. Equipment includes liquid handling robots; peptide and oligonucleotide synthesizers; multiple incubators and fast protein liquid chromatography systems; analytical instrumentation to characterize molecular interactions (surface plasmon resonance [SPR], isothermal titration calorimetry, analytical ultracentrifugation, circular dichroism with thermal control, etc.); NMR and mass spectrometers for small molecules; and equipment for macromolecular determinations (crystallization and visualization robots and a diffractometer). The DDSB-SR is co-directed by Drs. David Horne and John Williams, Professors in the Department of Molecular Medicine who are supported by a highly qualified staff. Since 2017, the DDSB-SR has synthesized more than 300 small molecules, 500 peptides, and 950 oligonucleotides (aptamers, GpC-conjugates, etc.). During that same period, >5000 crystallization and optimization trials were conducted, 1000s or crystals were screened for diffraction, >750 crystal structures/complexes were determined, and >600 SPR experiments, 35 in silico screening/molecular dynamics projects, and 23 HTS projects were conducted. DDSB-SR work has led to a significant technology portfolio involving 50 patents, 51 pending applications, and four exclusive licenses, as well as substantial sponsored research agreements (one valued at $876K) and royalty payments ($>1M). Members Utilization by %Revenue 2017–21: 99.5 Total (33 MCBC, 17.1 DCT, 23.2 CI, 25.8 HM, 0.3 CCPS) Publications by Members: 99, 36 with Impact Factor >10 Grants Supported: 46Total (1 ACS, 2 CIRM, 2 DoD, 1 LLS, 25 NCI of 36 NIH (28R01))