Drug Discovery and Structural Biology Core

药物发现与结构生物学资源共享 摘要 药物发现和结构生物学(DDSB)核心与希望之城的调查人员合作验证， 开发和优化新的治疗方法。为了实现这一点，DDSB提供了全面的 服务跨越计算方法；高通量筛选(HTS)；高级合成方法 生产小分子、多肽和具有挑战性的寡核苷酸；以及结构和生物物理方法。 这些服务为希望之城综合癌症中心(COHCCC)成员提供了具有凝聚力的 为快速、成功地推动他们的治疗开发努力取得有意义的成果提供了一个平台。 DDSB的所有主要设备和仪器都位于Flower大楼内。这包括一个 种类繁多的液体处理机器人；多肽和寡核苷酸合成器；多个孵化器和FAST 蛋白质生产和纯化用蛋白质液相色谱(FPLC)系统.分析仪器 为了表征分子相互作用(表面等离子激元共振[SPR]、等温滴定量热法[ITC]、 分析超速离心法、圆二向色性[CD]热控等)；核磁共振和质谱仪 小分子；大分子测定设备(结晶和可视化机器人 和一个衍射仪)。DDSB核心由大卫·霍恩和约翰·威廉姆斯博士共同指导，他们是 希望之城贝克曼研究所分子医学系，并得到高度支持 维护和操作设备的合格人员，同时为COHCCC研究人员提供培训 希望独立操作仪器的人。监督由跨学科的教职员工咨询提供 委员会，并通过年度调查提供用户反馈。自上次竞争性更新以来，核心 为CC成员发表的219篇文章做出贡献，为121名独立调查员提供服务，其中100名(83%)是 CC成员，并代表所有五个项目。在100个CC成员中，86个成员获得了同行审查的资金。在……里面 此外，自上次竞争更新以来，DDSB已经合成了300多个小分子， 500个多肽和950个寡核苷酸(适配子、GPC结合物等)。在同一时期， 进行了450次结晶和优化试验，筛选出250多个晶体进行衍射，超过 确定了40个新的晶体结构/配合物，并进行了300多个SPR实验，其中35个是在硅胶中进行的 筛选/分子动力学项目，开展了23个HTS项目。DDSB还开发了 合成方法和过程导致复杂小分子的大规模生产 GMP条件。来自DDSB的努力已经产生了32项技术/专利组合，涉及 76项专利(正在申请和允许)，4项许可，以及一份可观的赞助研究协议(&gt；100万美元)。

Drug Discovery and Structural Biology Shared Resource ABSTRACT The Drug Discovery and Structural Biology (DDSB) Core collaborates with City of Hope investigators to validate, develop, and optimize novel therapeutics. To accomplish this, the DDSB provides a comprehensive range of services spanning computational methods; high throughput screening (HTS); advanced synthetic methods to produce small molecules, peptides, and challenging oligonucleotides; and structural and biophysical methods. These services provide City of Hope Comprehensive Cancer Center (COHCCC) members with a cohesive platform to rapidly and successfully drive their therapeutic development efforts to meaningful outcomes. All major equipment and instrumentation for the DDSB is located in the Flower building. This includes an extensive array of liquid handling robots; peptide and oligonucleotide synthesizers; multiple incubators and fast protein liquid chromatography (FPLC) systems for protein production and purification; analytical instrumentation to characterize molecular interactions (surface plasmon resonance [SPR], isothermal titration calorimetry [ITC], analytical ultracentrifugation, circular dichroism [CD] 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 core is co-directed by Drs. David Horne and John Williams, Professors in the Department of Molecular Medicine at the Beckman Research Institute at City of Hope, and supported by highly qualified staff that maintain and operate the equipment while also providing training to COHCCC researchers who wish to operate instruments independently. Oversight is provided by an interdisciplinary faculty Advisory Committee, and user feedback through an annual survey. Since the last competitive renewal, the core contributed to 219 publications by CC members, served 121 unique investigators, 100 (83%) of whom were CC members and represent all five Programs. Of the 100 CC members, 86 had peer-reviewed funding. In addition, since the last competitive renewal, the DDSB has synthesized more than 300 small molecules, 500 peptides, and 950 oligonucleotides (aptamers, GpC-conjugates, etc.). During that same period, over 450 crystallization and optimization trials were conducted, over 250 crystals were screened for diffraction, over 40 novel crystal structures/complexes were determined, and over 300 SPR experiments, 35 in silico screening/molecular dynamics projects, and 23 HTS projects were conducted. The DDSB has also developed synthetic methods and processes leading to full-scale production of complex small molecules under GMP conditions. Efforts stemming from the DDSB have led to 32 technology/patent portfolios involving 76 patents (pending and allowed), four licenses, and a substantial sponsored research agreement (>$1M).