Multimodal contrastive learning for integrating molecular representations and cellular phenotypes in drug-target interaction prediction.

Abstract

Accurate prediction of drug-target interactions (DTIs) is fundamental to drug discovery and mechanistic understanding. While deep learning has advanced computational DTI prediction, most existing methods rely primarily on molecular structural representations, including drug structures and protein sequences, while overlooking cellular phenotypes that reflect downstream biological effects. Cell Painting enables high-content morphological profiling that captures systems-level responses to chemical and genetic perturbations but remains underutilized in DTI modeling. Integrating molecular information with cellular phenotypes offers an opportunity to improve both predictive performance and biological interpretability. We propose a two-stage contrastive learning framework integrating drug structures, protein sequences, and Cell Painting morphological profiles into a unified embedding space. Stage 1 learns modality-specific representations independently from structure-based and image-based data; Stage 2 aligns these via multi-positive contrastive learning to bridge molecular structural information with cellular phenotypes. Cross-modal retrieval achieves median Recall@10 values of 0.77 (random split) and 0.33 (scaffold split), outperforming bilinear and random baselines. In external DTI prediction on the BIOSNAP dataset, our model achieves an AUC of 0.92 with image-based representations and 0.90 under structure-only settings, surpassing existing methods. Model interpretation via integrated gradients reveals pathway-specific morphological signatures associated with drug targets, providing biologically interpretable insights into drug mechanisms. https://github.com/YJRubyLai/Unified-DTI.