Drug Design and Synthesis Core

摘要 药物设计和合成核心（DDSC）是COBRE靶向药物中心的关键组成部分。 治疗学（CTT）将使当前和未来的COBRE教师能够获得评估 开发针对特定靶点的化学生物学探针和/或候选药物的可行性， 到合成药物化学、计算化学的设备和专业知识， 开发和验证结合和功能测定。这些服务将使生物学家、生物化学家 药理学家可以获得药物靶点验证、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， 核心将追求以下具体目标：目标1。药物靶点可行性评估：DDSC将 在药物可药性方面提供对靶点的详细评价，即化学调节的可行性 目标靶标的功能活性或通过蛋白质-蛋白质相互作用的下游活性。目标二。 用于扩大命中率和优化先导化合物的合成药物化学：DDSC将提供合成药物化学， 通过采购已知的和商业的化学支持，为本COBRE申请中描述的项目提供化学支持 可用的配体（用作化学生物学探针），通过设计潜在靶点的合成路线， 通过体外或计算机筛选（Aim 3）和通过设计初始的化学文库鉴定的分子 用于命中扩展（结构-活性关系）和潜在客户优化目的的命中。目标3。结构 和/或基于配体的药物设计，用于命中鉴定、命中扩增和先导物优化： DDSC内的计算化学设施将为以下方面提供支持：1）计算机屏幕，以识别化学物质 所需生物靶标的起始点（命中）。2)通过计算的结构引导的引线优化 分析鉴定的命中物（和结构上相关的非活性物），促进特定类似物的合理设计 和化学文库以改善靶亲和力、选择性并赋予药物样物理化学性质。 目标4。体外结合和功能测定开发：DDSC将提供专业知识和资源 用于开发用于命中识别和先导物优化的结合和功能测定 阶段开发的检测方法将用于不同类型的筛选，包括高通量 在合作的HTS设施进行筛查。通过了解目标的可配位位点，包括 蛋白质-蛋白质相互作用的位点，将开发可用于确定 使用计算筛选发现的化合物的亲和力，以及在高- 吞吐量测试DDSC还将通过合成 所需的探针和示踪分子，如生物素或荧光素连接的配体，用于特定的药物靶标。

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.