Screening core

筛选核心

• 批准号: 10512620
• 负责人: Michelle Arkin
• 金额: $ 460.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/10512620
• 关键词: 2019-nCoV; Affinity; Antiviral Agents; Automation; Binding; Biochemistry; Biological Assay; Biology; Biophysics; COVID-19 pandemic; Catalogs; Cells; Cessation of life; Chemicals; Chemistry; Clinic; Development; Disulfides; Docking; Dose; Ensure; Family; Goals; In Vitro; Investigational Drugs; Lead; Libraries; Link; Mission; Morphologic artifacts; Oral; Outcome; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Process; Protein Biochemistry; Proteomics; RNA Viruses; Resources; Running; Scanning; Series; Structure-Activity Relationship; Surface Plasmon Resonance; Technology; Testing; Validation; Vesnarinone; Viral; Virus; Work; X-Ray Crystallography; analog; base; clinical candidate; clinical development; design; drug discovery; high throughput screening; in vivo; innovation; lead optimization; non-drug; novel therapeutics; pandemic disease; preclinical development; programs; response; screening; small molecule; small molecule libraries; stoichiometry; structural biology; synergism; virology; virtual; virtual screening

CORE 2: SCREENING SUMMARY The ongoing COVID-19 pandemic requires urgent development of new drugs, and furthermore highlights the critical need for the US to build an arsenal of broadly acting antiviral drugs for RNA viruses with pandemic potential. The QCRG Pandemic Response Program will develop 3-6 Optimized Leads for preclinical and clinical development by our pharmaceutical partners. To achieve this mission, the QCRG will prosecute fifteen antiviral targets in eight target classes across seven virus families. Six Projects will work with eight Cores, following a rigorous drug-discovery workflow from Target Characterization, Hit Identification, Hit-to-Lead optimization, and Lead Optimization. The Screening Core will drive Hit Identification, collaborating with Projects 1-6 to deliver 30-40 validated hits with preliminary structure-activity relationships (SAR) and defined mechanisms of action (MoA) to initiate Hit-to-Lead. During Hit-to-Lead, the Screening Core will further support Projects 1-6 to characterize MoA through biophysical assays and artifact-detecting screens, and to support selectivity panels and combination studies through assay automation. The Screening Core will work closely with the Projects, Biochemistry Core, Medicinal Chemistry Core, In Vitro Virology Core, and Proteomics Core to ensure that the most promising chemical series are developed into leads. To accomplish the discovery and validation of hits for Projects 1-6, the Screening Core will achieve the following Specific Aims: Aim 1. Identify chemical matter for twelve antiviral target classes in multiple viral families. Screening strategy for each Project will based on the target biology, assay-ability, and appropriate chemical libraries. At least two technologies, including HTS, ultra-large library docking, and fragment-based screening, will be applied to each project. Libraries available for the projects include 3 billion enumerated compounds for docking, ~255,000 diverse compounds for HTS, and ~6000 diverse fragments and 1600 mixed disulfides for fragment screens. Hits from SARS-CoV2 will be tested against a panel of homologous targets from other viruses. Aim 2. Validate active molecules through counter screens and biophysical assays. Molecules selected from screens can act through non-drug-like MoA. Projects 1-6 will utilize a suite of counter screens and biophysical assays designed to identify compound aggregation, binding reversibility (where desired), and binding stoichiometry. Cell-active compounds will be evaluated for phospholipidosis, a common antiviral artifact. Aim 3. Establish chemical tractability through fragment optimization and hit expansion. Validated hits transitioning from Hit Identification to Hit-to-Lead should have IC50/KD values in the low µM range, with preliminary SAR to indicate their chemical tractability. The compounds discovered through HTS and covalent approaches may already have affinities in this range; if so, chemistry-by-catalog and synthesis will focus on developing SAR. Fragments will likely require chemical optimization via fragment linking, merging, and design, guided by docking and structural biology. These Aims will yield 30-40 validated hits for optimization during Hit-to-Lead.

核心 2：筛选 概括 持续的 COVID-19 大流行需要迫切开发新药，并进一步凸显了 美国迫切需要建立一个针对大流行的 RNA 病毒的广泛作用的抗病毒药物库 QCRG 流行病应对计划将为临床前和临床前开发 3-6 个优化的先导药物。 我们的制药合作伙伴进行临床开发 为了实现这一使命，QCRG 将承诺 15 项。 七个病毒家族的八个目标类别的抗病毒目标将与八个核心一起工作， 遵循从目标表征、命中识别、命中到先导的严格药物发现工作流程 筛选核心将与项目合作推动命中识别。 1-6 提供 30-40 个经过验证的命中，并具有初步的结构-活性关系 (SAR) 和定义的机制 启动 Hit-to-Lead 的行动 (MoA) 在 Hit-to-Lead 期间，筛选核心将进一步支持项目 1-6。 通过生物物理测定和伪影检测屏幕表征 MoA，并支持选择性面板 筛选核心将与这些项目密切合作， 生物化学核心、药物化学核心、体外病毒学核心和蛋白质组学核心，以确保 最有前途的化学系列被开发成先导化合物，以完成命中的发现和验证。 对于项目 1-6，筛选核心将实现以下具体目标： 目标 1. 识别化学物质 每个项目的筛选策略将基于多个病毒家族中的十二个抗病毒靶标类别。 目标生物学、测定能力和适当的化学库，包括 HTS， 超大型文库对接，以及基于片段的筛选，将应用于每个项目可用的文库。 这些项目包括 30 亿种用于对接的列举化合物、约 255,000 种用于 HTS 的不同化合物，以及 将测试约 6000 个不同片段和 1600 个混合二硫化物，用于 SARS-CoV2 的片段筛选。 目标 2. 通过计数器验证活性分子。 从筛选中选择的分子可以通过非药物类 MoA 发挥作用。 项目 1-6 将利用一套计数器屏幕和生物物理测定来识别化合物 聚集、结合可逆性（如果需要）和结合化学计量将是细胞活性化合物。 评估磷脂沉积（一种常见的抗病毒伪影）。目标 3. 通过建立化学可处理性。 片段优化和命中扩展。已验证的命中从命中识别转变为命中引导。 应具有低 µM 范围内的 IC50/KD 值，并通过初步 SAR 来表明其化学可处理性。 通过 HTS 和共价方法发现的化合物可能已经在这个范围内具有亲和力；如果是这样， 按目录进行化学和合成将侧重于开发 SAR 可能需要化学物质。 在对接和结构生物学的指导下，通过片段连接、合并和设计进行优化。 将在 Hit-to-Lead 期间产生 30-40 个经过验证的命中以进行优化。