34亿分子库一键合成,用AI+自动化加速药物研发
onepot CORE -- an enumerated chemical space to streamline drug discovery, enabled by automated small molecule synthesis and AI
- 用AI规划合成路径,自动执行7类反应
- 34亿化合物可按需合成,成功率超90%
- 适合药企和科研机构快速获取多样性分子
早期药物研发中的“合成”环节仍是主要瓶颈:小分子合成耗时长、成本高,难以在多种化学类型间规模化自动化。现有枚举化学空间受限于周转时间长、反应范围窄及大量人工决策。本文提出首个onepot CORE化学空间,包含34亿个可合成分子及其对应的按需合成产品,依托自动化合成平台与AI化学家Phil实现从路线设计、液态处理到纯化全流程闭环。该空间基于药物化学常用7类反应构建,通过筛选供应商目录中的起始物料并枚举候选产物,再经机器学习可行性评估优先排序。验证显示合成成功率达90%以上,反应周期短,产物纯度与结构确认通过NMR验证,并在一系列DPP4抑制剂中证实可用于生物活性测试。onepot CORE为快速、可靠地获取多样化小分子提供了新路径。
原文摘要 · Abstract (English)
The design-make-test-analyze cycle in early-stage drug discovery remains constrained primarily by the "make" step: small-molecule synthesis is slow, costly, and difficult to scale or automate across diverse chemotypes. Enumerated chemical spaces aim to reduce this bottleneck by predefining synthesizable regions of chemical space from available building blocks and reliable reactions, yet existing commercial spaces are still limited by long turnaround times, narrow reaction scope, and substantial manual decision-making in route selection and execution. Here we present the first version of onepot CORE, an enumerated chemical space containing 3.4B molecules and corresponding on-demand synthesis product enabled by an automated synthesis platform and an AI chemist, Phil, that designs, executes, and analyzes experiments. onepot CORE is constructed by (i) selecting a reaction set commonly used in medicinal chemistry, (ii) sourcing and curating building blocks from supplier catalogs, (iii) enumerating candidate products, and (iv) applying ML-based feasibility assessment to prioritize compounds for robust execution. In the current release, the space is supported by seven reactions. We describe an end-to-end workflow - from route selection and automated liquid handling through workup and purification. We further report validation across operational metrics (success rate, timelines, purity, and identity), including NMR confirmation for a representative set of synthesized compounds and assay suitability demonstrated using a series of DPP4 inhibitors. Collectively, onepot CORE illustrates a path toward faster, more reliable access to diverse small molecules, supporting accelerated discovery in pharmaceuticals and beyond.
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