Screening core

核心2：筛选 摘要 正在进行的新冠肺炎大流行迫切需要开发新药，并进一步突显了 美国迫切需要建立针对大流行RNA病毒的广效抗病毒药物武器库 潜力。QCRG大流行应对计划将开发3-6个优化的临床前和 由我们的制药合作伙伴进行临床开发。为了完成这项任务，QCRG将起诉15名 七个病毒家族的八个靶标类别中的抗病毒靶标。六个项目将与八个核心一起工作， 遵循严格的药物发现工作流程，从目标表征、HIT识别、Hit-to-Lead 优化和领导优化。筛选核心将推动HIT识别，与项目合作 1-6提供30-40个具有初步结构-活性关系(SAR)和已定义机制的有效命中 行动(MOA)，以启动击打到领先。在Hit-to-Lead期间，筛选核心将进一步支持项目1-6 通过生物物理分析和人工产物检测屏幕确定MOA的特征，并支持选择性小组 以及通过分析自动化进行组合研究。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 最有希望的化学系列被开发成铅。来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 针对多个病毒家族的12个抗病毒靶标类别。每个项目的筛选策略将基于 关于目标生物学、分析能力和适当的化学库。至少有两项技术，包括HTS， 超大型文库对接和基于片段的筛选将应用于每个项目。可供使用的库 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 ~6000个不同的片段和1600个混合二硫化物用于片段筛选。SARS-CoV2病毒的命中将进行测试 对抗一组来自其他病毒的同源靶标。目标2.通过计数器验证活性分子 筛查和生物物理分析。从筛选中选择的分子可以通过非药物样的MOA发挥作用。 项目1-6将利用一套计数器筛查和生物物理分析方法来鉴定化合物 聚集、结合可逆性(在需要时)和结合化学计量学。细胞活性化合物将是 评估磷脂沉积症，一种常见的抗病毒人工制品。目标3.通过以下方式建立化学可处理性 碎片优化和命中扩展。验证的命中从命中识别过渡到命中到领先 IC50/Kd值应在低微米范围内，具有初步的SAR，以表明其化学处理能力。这个 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， 逐个目录的化学和合成将侧重于发展合成孔径雷达。碎片很可能需要化学物质 在对接和结构生物学的指导下，通过片段链接、合并和设计进行优化。这些目标 将在点击到领先的过程中产生30-40个有效命中率以进行优化。

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.