KANPM-DTA: improving drug-target affinity prediction with Kolmogorov-Arnold networks and pretrained models.

Abstract

Accurate drug-target affinity (DTA) prediction is critical for drug discovery and repurposing. However, existing models often struggle with generalizing to unseen drug-target pairs, lack interpretability, and fail to integrate heterogeneous biological features effectively. To overcome these challenges, we introduce KANPM-DTA, a deep learning framework designed to capture richer biochemical interactions and improve prediction reliability. Specifically, an ESM-guided protein graph construction strategy incorporates evolutionary and structural information to overcome underexplored protein representations. A gated fusion mechanism was employed to integrate drug-protein graph features, while linear attention captures cross-modal dependencies that enhance discriminative power. For the final affinity prediction, a Kolmogorov-Arnold network was used, offering a stronger nonlinear approximation and improved interpretability. Comprehensive experiments on benchmark datasets demonstrate that KANPM-DTA significantly outperforms state-of-the-art methods. On the Davis, KIBA, Metz, and BindingDB datasets, we achieved significant performance improvements under warm setting, with MSE reductions of 6.42%, 4.86%, 4.44%, and 5.46%, CI increases of 0.45%, 0.34%, 0.48%, and 0.80%, and $r_{m}^{2}$ gains of 1.85%, 0.90%, 0.84%, and 1.05%, respectively. Moreover, a case study on the epidermal growth factor receptor further highlights the effectiveness of KANPM-DTA in predicting DTAs for unknown drug-target pairs, emphasizing its potential for real-world applications in drug discovery. However, wet-lab validation is required to assess the applicability of the results.