提出多尺度信息瓶颈与协作注意力框架,提升药物设计中蛋白-配体相互作用建模能力。
MSCoD: An Enhanced Bayesian Updating Framework with Multi-Scale Information Bottleneck and Cooperative Attention for Structure-Based Drug Design
- 采用多尺度信息瓶颈实现多层次特征压缩与提取
- 在7XKJ数据集上对KRAS G12D靶点生成有效配体,优于现有方法
- 模块可迁移,提升GraphDTA在Davis和Kiba数据集上的性能
基于结构的药物设计(SBDD)利用蛋白质三维结构指导分子设计以增强结合亲和力。然而,捕捉跨多尺度的复杂蛋白-配体相互作用仍具挑战性,因现有方法常忽略其层次结构与内在不对称性。为此,本文提出MSCoD,一种基于贝叶斯更新的生成框架。其中,多尺度信息瓶颈(MSIB)实现多抽象层级的语义压缩,促进高效层次特征提取;多头协作注意力(MHCA)机制采用非对称的蛋白到配体注意力,捕捉多样相互作用类型,并缓解蛋白质与配体间的维度差异。实证研究显示,MSCoD在基准数据集上超越现有先进方法;对难靶点KRAS G12D(7XKJ)的案例研究验证其实际应用价值。此外,MSIB与MHCA模块具有可迁移性,在标准药物靶标亲和力预测基准(Davis与Kiba)上显著提升GraphDTA性能。代码与数据已公开于https://github.com/xulong0826/MSCoD。
原文摘要 · Abstract (English)
Structure-Based Drug Design (SBDD) is a powerful strategy in computational drug discovery, utilizing three-dimensional protein structures to guide the design of molecules with improved binding affinity. However, capturing complex protein-ligand interactions across multiple scales remains challenging, as current methods often overlook the hierarchical organization and intrinsic asymmetry of these interactions. To address these limitations, we propose MSCoD, a novel Bayesian updating-based generative framework for structure-based drug design. In our MSCoD, Multi-Scale Information Bottleneck (MSIB) was developed, which enables semantic compression at multiple abstraction levels for efficient hierarchical feature extraction. Furthermore, a multi-head cooperative attention (MHCA) mechanism was developed, which employs asymmetric protein-to-ligand attention to capture diverse interaction types while addressing the dimensionality disparity between proteins and ligands. Empirical studies showed that MSCoD outperforms state-of-the-art methods on the benchmark dataset. Its real-world applicability is confirmed by case studies on difficult targets like KRAS G12D (7XKJ). Additionally, the MSIB and MHCA modules prove transferable, boosting the performance of GraphDTA on standard drug target affinity prediction benchmarks (Davis and Kiba). The code and data underlying this article are freely available at https://github.com/xulong0826/MSCoD.
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