Prioritizing virtual screening with interpretable interaction fingerprints

Machine learning-based (ML) drug discovery success depends on molecular representation. Yet traditional molecular fingerprints omit the protein and pointers back to structural information that would enable better model interpretability. Therefore, we propose LUNA, a Python 3 toolkit that calculates and encodes protein-ligand interactions into new hashed fingerprints inspired by Extended Connectivity FingerPrint (ECFP): EIFP (Extended Interaction FingerPrint), FIFP (Functional Interaction FingerPrint), and Hybrid Interaction FingerPrint (HIFP). LUNA also provides visual strategies to make the fingerprints interpretable. We performed three major experiments exploring the fingerprints' use. First, we trained ML models to reproduce DOCK3.7 scores using 1 million docked Dopamine D4 complexes. We found that EIFP-4,096 performed (R² = 0.61) superior to related molecular and interaction fingerprints. Secondly, we used LUNA to support interpretable ML models. Finally, we demonstrate that interaction fingerprints can accurately identify similarities across molecular complexes that other fingerprints overlook.