用符号规则约束大模型生成药物分子,确保化学合理性。
Symbolic Neural Generation with Applications to Lead Discovery in Drug Design
- 结合归纳逻辑编程与大模型,用符号规则筛选生成分子
- 在未知靶点场景下生成分子的亲和力媲美临床候选药
- 生成结果可直接用于合成实验,适合药物研发人员
我们研究一类尚未充分探索的混合神经符号模型,即符号神经生成器(SNG),将符号学习与神经推理结合,构建满足形式正确性标准的数据生成器。在SNG中,符号学习者基于少量实例(有时仅一个)分析可行数据的逻辑规范,并以此约束神经生成器的条件输入,拒绝违反符号规范的样本。最终输出为一对 $(H, X)$:$H$ 是从数据中构建的可行实例符号描述,$X$ 是满足该描述的新生成实例集。我们提出了基于基集与纤维偏序集组合的系统语义。实现的SNG融合受限归纳逻辑编程(ILP)与大语言模型(LLM),并在早期药物设计任务上评估。重点在于生成的抑制剂分子及其符号描述。在已知靶点的基准测试中,性能与现有最先进方法相当;在靶点不明确的探索性任务中,生成分子的结合亲和力达到领先临床候选水平。专家认为符号规范可作为初步筛选工具,多个生成分子已被识别为具备合成与湿实验潜力。
原文摘要 · Abstract (English)
We investigate a relatively under-explored class of hybrid neurosymbolic models that integrate symbolic learning with neural reasoning to construct data generators meeting formal correctness criteria. In Symbolic Neural Generators (SNGs), symbolic learners examine logical specifications of feasible data from a small set of instances -- sometimes just one. Each specification in turn constrains the conditional information supplied to a neural-based generator, which rejects any instance violating the symbolic specification. Like other neurosymbolic approaches, SNG exploits the complementary strengths of symbolic and neural methods. The outcome of an SNG is a pair $(H, X)$, where $H$ is a symbolic description of feasible instances constructed from data, and $X$ a set of generated new instances that satisfy the description. We introduce a semantics for such systems, based on the construction of appropriate base and fibre partially-ordered sets combined into an overall partial order. We implement an SNG combining a restricted form of Inductive Logic Programming (ILP) with a large language model (LLM) and evaluate it on early-stage drug design. Our main interest is the description and the set of potential inhibitor molecules generated by the SNG. On benchmark problems -- where drug targets are well understood -- SNG performance is statistically comparable to state-of-the-art methods. On exploratory problems with poorly understood targets, generated molecules exhibit binding affinities on par with leading clinical candidates. Experts further find the symbolic specifications useful as preliminary filters, with several generated molecules identified as viable for synthesis and wet-lab testing.
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