BERT4DTI : BERT-based Model for Predicting Drug-Protein Interactions

Abstract

Understanding how drugs interact with protein targets is fundamental to drug discovery, drug repurposing and the early identification of promising therapeutic candidates before costly experimental testing. Sequence-based DTI models face three practical limitations: labelled interactions are scarce and unevenly distributed, large pretrained chemical and protein encoders are expensive to fine-tune end-to-end, and independently encoded sequences do not capture pair-specific dependencies. We present BERT4DTI, which encodes SMILES strings with ChemBERTa and amino-acid sequences with ProtBERT, applies bidirectional mutual attention between token-level representations, and classifies the resulting interaction features using convolutional layers and a multilayer perceptron. To reduce trainable size, ProtBERT is truncated to 18 retained layers and only the last two layers of each encoder are fine-tuned. On BIOSNAP, DAVIS and BindingDB, BERT4DTI is competitive, achieving the best ROC-AUC and PR-AUC on BIOSNAP and the highest sensitivity on all three benchmarks. An ablation on DAVIS shows that mutual attention improves PR-AUC and specificity. With 125M trainable parameters compared with 353M for full BERT fine-tuning, BERT4DTI provides a favourable performance-parameter trade-off for sequence-based DTI screening, while leaving runtime profiling, calibration and leakage-audited validation for future work.