Drug Design and Synthesis Core

药物设计与合成核心

• 批准号: 10221717
• 负责人: Campbell McInnes
• 金额: $ 16.39万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221717
• 关键词: Active Sites; Affinity; Antibody-drug conjugates; Binding; Biological; Biological Assay; Biological Process; Biological Testing; Biology; Biotin; Centers of Research Excellence; Chemicals; Clinic; Computer Analysis; Crystallization; DNA; Development; Distant; Docking; Drug Design; Drug Kinetics; Drug Targeting; Equipment; Evaluation; Faculty; Fluorescein; Fluorescence; Fluorescence Polarization; Future; Goals; In Vitro; Intellectual Property; Knowledge; Ligands; Link; Miniaturization; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preclinical Drug Development; Property; Proteins; Resource Development; Route; Services; Site; Source; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Synthesis Chemistry; Testing; Toxic effect; Tracer; Tryptophan; Validation; analog; assay development; base; chemical synthesis; computational chemistry; design; drug candidate; drug discovery; drug synthesis; high throughput screening; improved; in silico; in vitro Assay; interest; lead optimization; pharmacophore; protein protein interaction; screening; small molecule; small molecule libraries; structural biology; targeted treatment; ubiquitin-protein ligase; validation studies; virtual screening

ABSTRACT The Drug Design and Synthesis Core (DDSC), a key component of the COBRE Center for Targeted Therapeutics (CTT), will enable current and future COBRE faculty to access expertise in assessing the feasibility of developing a chemical biology probe and/or drug candidate for a particular target, provide access to equipment and expertise in synthetic medicinal chemistry, computational chemistry and lastly in the development and validation of binding and functional assays. These services will allow biologists, biochemists and pharmacologists access to key functional molecules that they require for drug target validation, studies using a chemical biology probe and furthermore in preclinical drug development studies. Towards this goal, the Core will pursue the following specific aims: Aim 1. Drug Target Feasibility Assessment: The DDSC will provide a detailed evaluation of targets in terms of druggability, i.e. the feasibility of chemically modulating functional activity of the target of interest or downstream activity through protein-protein interactions. Aim 2. Synthetic Medicinal Chemistry for Hit Expansion and Lead Optimization: The DDSC will provide synthetic chemistry support for the projects described in this COBRE application by sourcing known and commercially available ligands (for use as chemical biology probes), by designing synthesis routes for potential target molecules identified through in vitro or in silico screening (Aim 3) and by designing chemical libraries of initial hits for hit expansion (structure-activity relationships) and lead optimization purposes. Aim 3. Structure and/or Ligand Based Drug Design for hit identification, hit expansion and lead optimization: The computational chemistry facility within the DDSC will provide support for 1) in silico screens to identify chemical starting points (hits) for desired biological targets. 2) Structure-guided lead optimization through computational analysis of identified hits (and structurally related inactives) facilitating rational design of specific analogues and chemical libraries to improve target affinity, selectivity and to impart drug-like physicochemical properties. Aim 4. In vitro binding and functional assay development: The DDSC will provide expertise and resources for development of binding and functional assays that will serve in the hit identification and lead optimization stages. The developed assays will be used for different types of screenings, including high-throughput screening (HTS) at the collaborating HTS facility. Through knowledge of a target’s ligandable sites including sites of protein-protein interactions, in vitro binding assays will be developed that can be used for determining the affinity of compounds discovered using computational screening and also for miniaturization in high- throughput testing. Assay development will also be supported by the DDSC through the synthesis of the required probes and tracer molecules such as biotin or fluorescein linked ligands for a particular drug target.

摘要 药物设计和合成核心(DDSC)，科布雷靶向中心的关键组成部分 治疗学(CTT)，将使现有和未来的Cobre教职员工能够获得评估 为特定目标开发化学生物学探针和/或候选药物的可行性，提供了 到合成药物化学、计算化学的设备和专业知识，最后是 结合分析和功能分析的开发和验证。这些服务将允许生物学家、生物化学家 和药理学家获得他们需要的关键功能分子，以验证药物靶标，研究 使用化学生物学探针，并进一步用于临床前药物开发研究。为了实现这一目标， CORE将追求以下具体目标：目标1.药物靶标可行性评估：DDSC将 根据可制药性对目标进行详细评估，即化学调制的可行性 目标蛋白的功能活性或通过蛋白质-蛋白质相互作用的下游活性。目标2. 用于HIT扩展和领先优化的合成药物化学：DDSC将提供合成 通过已知和商业来源为本Cobre申请中描述的项目提供化学支持 可用配体(用作化学生物探针)，通过为潜在目标设计合成路线 通过体外或电子筛选鉴定的分子(目标3)和通过设计初始的化学文库 命中扩展(结构-活动关系)和引导优化目的的命中。目标3.结构 和/或基于配基的药物设计，用于HIT识别、HIT扩展和引线优化： DDSC内的计算化学设施将为1)在硅胶屏幕上识别化学物质提供支持 所需生物目标的起点(命中率)。2)通过计算实现结构制导的引线优化 分析已识别的HITS(和结构上相关的非活性物质)，促进特定类似物的合理设计 和化学库，以提高靶向亲和力和选择性，并赋予药物样的物理化学性质。 目的4.体外结合和功能分析的发展：DDSC将提供专业知识和资源 用于开发将用于HIT鉴定和引线优化的绑定和功能分析 各阶段。开发的分析方法将用于不同类型的筛选，包括高通量 在合作的HTS设施中进行筛选(HTS)。通过了解目标的可配基部位，包括 蛋白质-蛋白质相互作用的部位，体外结合分析将被开发，可用于确定 利用计算筛选发现的化合物的亲和力，以及在高密度脂蛋白中的小型化。 吞吐量测试。化验开发也将得到DDSC的支持，通过合成 特定药物靶标所需的探针和示踪分子，如生物素或荧光素连接的配体。