BiLSTM-Powered Bilinear Attention for Protein–Ligand Prediction

Rapid and accurate prediction of protein-ligand bindings is essential for drug discovery. While generative AI has driven rapid advancements in structure-based approaches, sequence-based methods remain significantly faster and more cost-effective. Here, we present a weakly supervised deep learning framework integrating graph convolutional networks (GCN) for molecular encoding and bidirectional long short-term memory (BiLSTM) for protein modeling. The latter represents long-range dependencies better than the widely used convolutional neural network (CNN). Leveraging a bilinear attention network (BAN), this model learns protein-ligand pairwise interactions without requiring three-dimensional structural supervision. By using the publicly available BindingDB dataset, the model was trained, solely on affinity labels, and successfully classified binder and non-binders with AUROC of 0.96 and an AUPRC of 0.95. The model generates interpretable attention maps that serve as a “GPS” to locate binding sites. Remarkably, despite the lack of structural training data, it can pinpoint key contact residues confirmed by crystal structures. Our method could function as a scalable filter for giga-scale libraries, allowing rapid screening of drug candidates with direct structural insights into the protein-ligand interface.