Enhancing Generalizability in Protein–Ligand Binding Affinity Prediction with Multimodal Contrastive Learning

Improving the generalization ability of scoring functions remains a major challenge in protein–ligand binding affinity prediction. Many machine learning methods are limited by their reliance on single-modal representations, hindering a comprehensive understanding of protein–ligand interactions. We introduce a graph-neural-network-based scoring function that utilizes a triplet contrastive learning loss to improve protein–ligand representations. In this model, three-dimensional complex representations and the fusion of two-dimensional ligand and coarse-grained pocket representations converge while distancing from decoy representations in latent space. After rigorous validation on multiple external data sets, our model exhibits commendable generalization capabilities compared to those of other deep learning-based scoring functions, marking it as a promising tool in the realm of drug discovery. In the future, our training framework can be extended to other biophysical- and biochemical-related problems such as protein–protein interaction and protein mutation prediction.