MSCoD: An Enhanced Bayesian Updating Framework with Multi-Scale Information Bottleneck and Cooperative Attention for Structure-Based Drug Design

Abstract

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.