提出碎片化方法,让合成规划速度提升至二次方复杂度。
FragmentRetro: A Quadratic Retrosynthetic Method Based on Fragmentation Algorithms
- 用碎片算法递归组合分子片段,快速生成候选前体
- 在三大数据集上解题率高,比传统方法快且能处理难题
- 适合需要高效生成起点的自动化合成规划场景
逆合成是将目标分子分解为简单前体的关键步骤,对计算机辅助合成规划(CASP)至关重要。现有树搜索方法常面临指数级计算复杂度问题。本文提出FragmentRetro,一种基于碎片化算法(BRICS与r-BRICS)的新方法,结合库存感知探索与模式指纹筛选,实现二次方复杂度 $O(h^2)$。该方法递归组合分子片段,并验证其是否存在于构建块集合中,提供碎片组合作为逆合成解。首次对逆合成方法进行形式化分析:树搜索为 $O(b^h)$,DirectMultiStep 为 $O(h^6)$,而FragmentRetro达到 $O(h^2)$,其中 $h$ 为目标分子重原子数,$b$ 为树搜索分支因子。在PaRoutes、USPTO-190及天然产物数据集上的评估显示,FragmentRetro在保持竞争力运行时间的同时,取得高解题率,甚至在树搜索失败的情况下仍可求解。指纹筛选显著降低子结构匹配复杂度。尽管聚焦于高效识别碎片解而非完整反应路径,其计算优势与生成战略起始候选的能力,使其成为可扩展自动化合成规划的强大基础组件。
原文摘要 · Abstract (English)
Retrosynthesis, the process of deconstructing a target molecule into simpler precursors, is crucial for computer-aided synthesis planning (CASP). Widely adopted tree-search methods often suffer from exponential computational complexity. In this work, we introduce FragmentRetro, a novel retrosynthetic method that leverages fragmentation algorithms, specifically BRICS and r-BRICS, combined with stock-aware exploration and pattern fingerprint screening to achieve quadratic complexity. FragmentRetro recursively combines molecular fragments and verifies their presence in a building block set, providing sets of fragment combinations as retrosynthetic solutions. We present the first formal computational analysis of retrosynthetic methods, showing that tree search exhibits exponential complexity $O(b^h)$, DirectMultiStep scales as $O(h^6)$, and FragmentRetro achieves $O(h^2)$, where $h$ represents the number of heavy atoms in the target molecule and $b$ is the branching factor for tree search. Evaluations on PaRoutes, USPTO-190, and natural products demonstrate that FragmentRetro achieves high solved rates with competitive runtime, including cases where tree search fails. The method benefits from fingerprint screening, which significantly reduces substructure matching complexity. While FragmentRetro focuses on efficiently identifying fragment-based solutions rather than full reaction pathways, its computational advantages and ability to generate strategic starting candidates establish it as a powerful foundational component for scalable and automated synthesis planning.
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