Drug Design and Synthesis Core

药物设计与合成核心

基本信息

批准号：
9978919
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
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9978919
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

项目摘要

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.

抽象的药物设计和合成核心（DDSC），靶标的鞋垫中心的关键组成部分治疗学（CTT），将使当前和未来的家族能够获得评估的专业知识为特定目标开发化学生物学探针和/或候选药物的可行性，提供访问用于合成药物，计算化学的设备和专业知识，最后结合和功能测定的开发和验证。这些服务将允许生物学家，生物化学家研究医生可以访问他们需要进行药物靶向验证所需的关键功能分子在临床前药物开发研究中使用化学生物学探针，并在此外。朝着这个目标，核心将追求以下特定目标：目标1。药物目标可行性评估：DDSC将提供有关可药用的目标的详细评估，即化学调节的可行性通过蛋白质 - 蛋白质相互作用的目标或下游活性目标的功能活性。目标2。合成药物化学以进行HIT膨胀和铅优化：DDSC将提供合成通过在已知和商业上采购该毛绒应用程序中描述的项目的化学支持可用的配体（用于化学生物学问题），通过设计潜在目标的合成途径通过体外或计算机筛选中鉴定的分子（AIM 3）和设计初始文库点击命中率扩展（结构活性关系）和铅优化目的。目标3。结构和/或基于配体的药物设计，用于命中识别，命中扩展和铅优化： DDSC内的计算化学设施将为1）在计算机屏幕中提供支持以识别化学所需生物学靶标的起点（命中）。 2）结构通过计算引导的铅优化分析已确定的命中（以及与结构相关的无活跃物）促进特定类似物的合理设计和化学文库以提高靶标亲和力，选择性和赋予药物样物理特性。目标4。体外约束和功能评估开发：DDSC将提供专业知识和资源用于开发将在命中识别和铅优化的结合和功能测定阶段。开发的测定将用于不同类型的筛选，包括高通量在合作的HTS设施中筛选（HTS）。通过了解目标的可韧带网站将开发可用于确定的蛋白质蛋白相互作用的位点，体外结合测定法使用计算筛选发现的化合物的亲和力以及高 - 吞吐量测试。 DDSC也将通过合成来支持测定开发所需的问题和示踪剂分子，例如生物素或荧光素连接的特定药物靶标。