BBBP_Atlas: Unified Interpretable Modeling of Blood Brain Barrier Permeability across Small Molecules and Peptides

Abstract

Accurate prediction of blood-brain barrier permeability (BBBP) is essential for central nervous system drug discovery, yet existing models are often limited by their reliance on predefined physicochemical descriptors, small-molecule-centered training sets, or conformation-dependent representations, which restricts their transferability across chemically diverse modalities especially peptides. In addition, publicly available BBBP datasets remain fragmented, inconsistently standardized, and weakly controlled for molecular redundancy, increasing the risk of data leakage and overestimated model performance. In this study, we propose BBBP-Atlas, a structure-aware BBB permeability prediction model designed for unified modeling of small molecules and peptides with the first cross-modal dataset OmniBBBP. Designed to bypass descriptor and conformation dependencies, our model represents standardized molecular structures as atom-level graphs to capture local atom-bond environments and long-range topological dependencies associated with BBB transport. This design enables direct learning of structure-permeability relationships from molecular topology. For model training and evaluation, we curated a cross-modal, redundancy-filtered database OmniBBBP that seamlessly unifies small molecules and complex peptides, containing 10,218 unique compounds with 9,316 small molecules and 902 peptides. BBBP-Atlas achieved an accuracy of 0.8914 and an MCC of 0.7678 on the independent test set. On a balanced external benchmark of 200 compounds, our model reached an AUC of 0.9108, an accuracy of 0.8500, and an MCC of 0.7000, outperforming LightBBB by an absolute MCC gain of 6%. Case studies further showed that BBBP-Atlas captured clinically meaningful BBB permeability patterns, correctly identifying lorlatinib as BBB-permeable and vancomycin as BBB-impermeable with high confidence. The OmniBBBP-backed BBBP-Atlas offers a versatile and cross-modal approach for single-compound prediction, batch screening, and dataset exploration for CNS drug discovery. BBBP-Atlas is available at https://cadd.drugflow.com/bbbp/.