Core B: Discovery Core

核心B：发现核心

• 批准号: 10513681
• 负责人: Kenneth Hugh Pearce
• 金额: $ 938.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513681
• 关键词: Antiviral Agents; Binding; Binding Sites; Biological Assay; Biology; Biophysics; Bromodomain; Caspase; Chemicals; Communities; Complement; Computing Methodologies; DNA; DNA-Directed RNA Polymerase; Data; Development; Diamond; Drug Targeting; Enzymatic Biochemistry; Enzymes; Family; Generations; Human; Industrialization; Lead; Libraries; Ligands; Light; Methodology; Methyltransferase; Molecular Target; Pharmaceutical Chemistry; Pharmacology; Phase; Probability; Protein Binding Domain; Protein Family; Proteins; RNA Helicase; Recombinant Proteins; Recombinants; Scientist; Serine Protease; Site; Source; Structure; Structure-Activity Relationship; Technology; Tertiary Protein Structure; Trust; Validation; Viral; Viral Physiology; Virus; WD Repeat; Work; X-Ray Crystallography; antiviral drug development; assay development; base; clinical candidate; deep learning; design; drug candidate; drug discovery; experience; innovation; knowledge base; lead optimization; learning strategy; new therapeutic target; novel; open data; pandemic disease; programs; protein expression; screening; structural genomics; tool; Antiviral Agents; Binding; Binding Sites; Biological Assay; Biology; Biophysics; Bromodomain; Caspase; Chemicals; Communities; Complement; Computing Methodologies; DNA; DNA-Directed RNA Polymerase; Data; Development; Diamond; Drug Targeting; Enzymatic Biochemistry; Enzymes; Family; Generations; Human; Industrialization; Lead; Libraries; Ligands; Light; Methodology; Methyltransferase; Molecular Target; Pharmaceutical Chemistry; Pharmacology; Phase; Probability; Protein Binding Domain; Protein Family; Proteins; RNA Helicase; Recombinant Proteins; Recombinants; Scientist; Serine Protease; Site; Source; Structure; Structure-Activity Relationship; Technology; Tertiary Protein Structure; Trust; Validation; Viral; Viral Physiology; Virus; WD Repeat; Work; X-Ray Crystallography; antiviral drug development; assay development; base; clinical candidate; deep learning; design; drug candidate; drug discovery; experience; innovation; knowledge base; lead optimization; learning strategy; new therapeutic target; novel; open data; pandemic disease; programs; protein expression; screening; structural genomics; tool

ABSTRACT The READDI AViDD Center (READDI-AC) will create new broad spectrum direct acting antiviral (DAA) drug candidates to treat current and emerging pandemic threats. Discovery Core B will serve as the discovery engine for identification of new inhibitory chemical matter (hits), validation of chemically tractable molecular target sites, and will support the optimization of hits to pharmacological tools (chemical probes) and Leads by MedChem Core D. Together and also with Projects 2-5 and Enzymology Core C, we will feed a pipeline of Lead compounds to the Project teams and industrial partners to complement existing assets. This proposal brings a world-leading team, all affiliated with, or collaborators of, the Structural Genomics Consortium (SGC). The SGC is an open science partnership that supports the pharmacological identification of new drug targets and is a world leader in the generation, characterization, and distribution of high-quality chemical probes – one of the most impactful tools for target validation, and an important early milestone in drug discovery. The SGC uses a protein family (aka target class) approach to drive efficiency in development of chemical probes. Through our strong experience with open science and protein family chemical probe development, Discovery Core B together with MedChem Core D are poised to tackle the READDI-AC portfolio of targets, which spans three main families of viral enzymes: RNA polymerases, RNA helicases, and cysteine and serine proteases. Discovery Core B aims to prime the READI-AC and global DAA drug discovery pipeline by generating high- quality chemical probes that will accelerate the development of innovative direct acting anti-viral drugs. Aim 1. Portfolio creation: The Discovery Core B will work closely with the Enzymology Core C, MedChem Core D and Projects 2-5 to select a portfolio of tractable DAA target sites across the four virus families and three main enzyme target protein families, such that eight target sites enter the hit discovery phase each year. Aim 2. Hit discovery and Validation: The Discovery Core B will use both diversity- and knowledge-based HTS for hit discovery using purified recombinant enzyme in one or more of >10 assay formats. Hits will be validated though a robust workflow to yield a data package (Hit CV) for consideration for further optimization. Aim 3. Hit-to-Probe (H2P) activities. Discovery Core B will support MedChem Core D with rapid execution of assays and X-ray crystallography to support structure-guided SAR of compounds made and/or designed in MedChem Core D. We will also evaluate viral-active compounds for selectivity against related human enzymes. Discovery Core B will deliver at least 12 high-quality Hit CVs every year, for consideration by Adman Core A as starting points for Hit-to-Probe/Lead optimization, and support the Hit-to-Probe activities by the Projects. All chemical probes will be made openly available to the scientific community for use as pharmacological tools.

抽象的 Readdi Avidd中心（READDI-AC）将创建新的广谱直接表演抗病毒药（DAA）药物 候选人治疗当前和新兴的大流行威胁。发现核心B将作为发现 用于鉴定新抑制性化学物质（hits）的发动机，可化学障碍分子的验证 目标站点，并将支持对药品工具（化学问题）的击球优化，并引导 Medchem核心D.一起，以及项目2-5和酶学核心C，我们将喂养一条管道 将化合物带给项目团队和工业合作伙伴，以完成现有资产。 该建议带来了一个世界领先的团队，所有团队都与结构性基因组学的合作者或合作者相关联 财团（SGC）。 SGC是一种开放科学合作伙伴关系，支持药物识别 新药目标，是高质量的一代，表征和分布的世界领导者 化学问题 - 目标验证最有影响力的工具之一，也是药物的重要早期里程碑 发现。 SGC使用蛋白质家族（又称目标类）方法来提高效率 化学问题。通过我们在开放科学和蛋白质家族化学探针方面的丰富经验 开发，发现核心B与Medchem Core D一起被中毒以应对REDDI-AC投资组合 跨越病毒酶的三个主要家族的靶标：RNA聚合酶，RNA解旋酶和 半胱氨酸和串行蛋白酶。 Discovery Core B旨在通过产生高级AC和全球DAA药物发现管道质量 优质的化学问题将加速创新的直接作用抗病毒药物的发展。 目标1。投资组合创建：发现核心B将与酶学C核C，Medchem紧密合作 核心D和项目2-5，以选择四个病毒家族的可访问DAA目标站点的投资组合 三个主要的酶靶蛋白家族，使得八个目标位点每年进入HIT发现阶段。 目标2。命中发现和验证：发现核心B将同时使用多样性和基于知识 使用纯化的重组酶以> 10种测定格式的一种或多个进行纯化的重组酶进行HTS。命中将是 通过强大的工作流进行了验证，以产生数据包（HIT CV）以进行进一步优化。 目标3。撞击（H2P）活动。 Discovery Core B将通过快速执行支持Medchem Core D 测定和X射线晶体学以支持制成和/或设计的化合物的结构引导SAR MedchemCoreD。我们还将评估病毒活性化合物，以实现针对相关人类酶的选择性。 Discovery Core B每年将至少提供12个高质量的HIT CVS，以供Adman Core A 作为命中访问/线索优化的起点，并支持项目的访问活动。全部 化学问题将公开向科学界公开用作药品工具。