Bridging predictive reliability and explainability: a multi-representation deep learning framework for chemical space...

Convergence of chemical and biological space into a unified decision space requires coordinated interactions across the triad- molecular representations, learning algorithms, and explainability. This study establishes a benchmarking framework for Virtual Screening (VS) that integrates this triad to enable consistent, predictive, and interpretable modelling of complex immune-related bioassays. The study employed a wide range of Machine Learning (ML) and Deep Learning (DL) models across three molecular input modalities-descriptors, images, and graphs-while prioritizing predictive reliability and model interpretability. Among classical ML models, Support Vector Machines (SVM) demonstrated the strongest overall performance, while the AttentiveFP architecture outperformed other DL models. Beyond identifying context-specific optimal VS networks, this study derives latent learned concepts that support subsequent hypothesis generation and experimental validation of the interaction between immune targets and ligands.Scientific contributionThis study establishes a benchmarking framework for virtual screening of immune targets by curating representative bioassay datasets, systematically evaluating multiple molecular representations and learning algorithms, and integrating explainability into the best-performing models. By combining Concept Whitening with the AttentiveFP architecture, we introduce an integrated explainable DL framework that maintains predictive reliability while enabling alignment and separation of domain-specific concepts for immune-target virtual screening. In addition, the study highlights the potential for decision- and logical-level model ensembling, identifies target-specific concept relevance in decision-making, and demonstrates the relationship between data characteristics and model behaviour.