Screening core

核心2：筛选

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.