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

Predicting Drug-Target Interactions~(DTIs) is a central task in computational drug discovery, with direct applications in virtual screening, drug repurposing, and therapeutic candidate prioritization. Although recent deep learning methods have improved DTI prediction, many sequence-based models still process drugs and proteins independently and only combine their representations at a late prediction stage. This limits their ability to explicitly model cross-molecular dependencies between chemical substructures and protein sequence regions. In this paper, we propose a sequence-only DTI prediction architecture that combines two pre-trained language models, ChemBERTa for drug SMILES strings and ESM-2 for protein amino acid sequences, with a hierarchical interaction module. The proposed model first extracts contextual representations using pre-trained encoders, then applies 1D convolutional layers to condense local sequence patterns, followed by a sequential bidirectional cross-attention mechanism inspired by the induced-fit view of molecular recognition. Finally, attention-based pooling constructs fixed-size interaction-aware vectors for binary prediction. Experiments on BIOSNAP, Davis, and BindingDB show that the proposed model achieves the best performance on BIOSNAP, matches the best AUROC on Davis, and remains competitive on BindingDB while using only 25.2 million trainable parameters. Ablation results confirm the contribution of both the CNN and cross-attention modules, and cold-start experiments indicate promising generalization to unseen proteins and drugs.

Accurate prediction of drug-target interactions (DTI) is critical for drug discovery. Existing methods often rely on single-modal representations (e.g., sequences or graphs) or combine only two modalities, overlooking 3D structural features. To address this challenge, we propose TriMod-DTI, a triple-modal contrastive learning framework that incorporates 1D sequences, 2D graphs, and 3D structures of drugs and proteins, obtaining the universal and complementary feature representations for DTI prediction. We design a Feature Extractor to capture drug and target features across the three modalities, thereby enriching their representations. We further propose a triple-modal contrastive learning strategy to align different modal representations of the same drug or protein in the latent space. By constructing cross-modal positive and negative sample pairs, this approach enhances the model's discriminative ability. Experiments on three benchmark datasets demonstrate that TriMod-DTI outperforms state-of-the-art methods. The ablation studies validate the contributions of each modality. Moreover, case studies highlight its practical potential for DTI prediction and drug discovery.

Public drug-protein bioactivity resources commonly identify targets by UniProt accession, although one accession may represent distinct experimental sequences. We present Curate-DTI, a construct-aware dataset derived from the 1 July 2026 BindingDB export, with IC50, Ki, Kd and EC50 processed independently. The release contains 2,919,717 measurements, 1,291,872 standardized ligands, 9,668 sequence-defined protein entities and 2,275,683 endpoint-specific interactions spanning 8,336 reviewed UniProt accessions. Protein entities combine the accession with the reported experimental sequence, preserving constructs that accession-only processing would merge. Across the four endpoints, 4,204 endpoint-specific ligand-accession groups showed different classification labels across sequence-defined protein entities. Exact and inequality-qualified observations provide relation-aware classification evidence, whereas regression targets use exact values only. Connected Parquet tables preserve individual measurements, standardized structures, protein sequences, aggregated interactions and available assay and source provenance. The resource supports endpoint-specific classification and regression while allowing users to select molecular representations, protein representations and evaluation splits. Preprocessing code, a column dictionary, exclusion reports and validation summaries accompany the release.