Core D: Medicinal Chemistry Core

摘要 MedChem Core D将主要专注于非核苷直接作用抗病毒(DAA)导联的交付 以补充READDI-AC产品组合中现有的化学资产。 为了实现这一目标，MedChem Core D将创建高质量的非核苷小分子探针 强大的抗病毒活性和类药物药代动力学特性。MedChem Core D由以下部分组成 美国和英国结构基因组联盟的实验和计算化学家 (SGC)，在开发和与科学界自由共享方面有一流的记录 化学探针和小分子药物线索。所有由MedChem Core D产生的化学探针将 向AViDD中心和更广泛的研究社区提供，不受知识产权的限制，以实现 对每种DAA机制的治疗潜力和应用范围进行深入科学研究。 MedChem Core D特别适合利用Open的创新和生产力收益 支持其具体目标的科学： 目标1.Hit Discovery支持：MedChem Core D将支持高通量屏幕的Hit分类 由发现核心B执行，并通过组装目标类化学品进行种子命中发现工作 文库来自基于结构的虚拟筛选(VS)和从头设计方法。 目标2.命中探测：MedChem Core D将迭代地设计一组具有物理化学特性的类药物类似物 与细胞活动相一致的特性。类似物将在一系列分析中进行评估，以解决 目标亲和力、细胞活性、ADME特性和病毒复制检测的有效性。最终的探测将 被广泛描述以支持他们的MOA和有效性，并被评为体内PK以完成 销售线索简历。SGC开放式化学网络将用于为这些目标提供额外的能力 这产生了超过两部确认的热门系列剧。 MedChem Core D的总体目标是提供至少16个具有强大抗干扰性的化学探测器 病毒活性和类似药物的特性。这些探测将作为领先候选人的起点 通过项目进行优化。

ABSTRACT MedChem Core D will focus primarily on the delivery of non-nucleoside direct acting antiviral (DAA) leads to the Projects to complement the existing chemical assets in the READDI-AC portfolio. To achieve this goal MedChem Core D will create high-quality non-nucleoside small molecule probes with robust antiviral activity and drug-like pharmacokinetic properties. MedChem Core D is composed of experimental and computational chemists at the US and UK sites of the Structural Genomic Consortium (SGC) who have a track record in developing and sharing freely with the scientific community first-in-class chemical probes and small molecule drug leads. All chemical probes generated by MedChem Core D will be made available to the AViDD centers and the broader research community, unrestricted by IP, to enable deep scientific study of both therapeutic potential as well as breadth of utility of each DAA mechanism. MedChem Core D is particularly well placed to harness the innovation and productivity gains of open science to support its specific aims: Aim 1. Hit Discovery Support: MedChem Core D will support the hit triage of high throughput screens performed by Discovery Core B and seed hit discovery efforts through assembly of target class chemical libraries from structure-based virtual screening (VS) and de novo design approaches. Aim 2. Hit to probe: MedChem Core D will iteratively design sets of drug-like analogs with physiochemical properties consistent with cellular activity. Analogs will be assessed in a hierarchy of assays to address target affinity, cellular activity, ADME properties, and efficacy in virus replication assays. Final probes will be extensively characterized to support their MoA and efficacy and be profiled for in vivo PK to complete a Lead CV. The SGC Open Chemistry Network will be used to provide additional capacity for those targets that yield more than two confirmed hit series. The overall goal of the MedChem Core D is to deliver a minimum of 16 chemical probes with robust anti- viral activity and drug-like properties. These probes will serve as starting points for lead-to-candidate optimization by the Projects.