Deep Learning for Blood-Brain Barrier Permeability Prediction: From Discriminative Models to Mechanism-Aware Design

Abstract

Predicting whether a molecule can cross the blood-brain barrier (BBB) is a key step in early-stage neuro-pharmaceutical design, directly influencing the efficiency and success rate of drug development. Traditional methods based on physicochemical properties are prone to systematic misjudgements due to their reliance on previous empirical evidence. Early machine learning (ML) models, although data-driven, often suffer from limited capacity, poor generalization, and insufficient interpretability. In recent years, more advanced models have become essential tools for predicting BBB permeability and guiding related drug design, owing to their ability to simulate molecular structures and capture complex biological mechanisms. This article systematically reviews the evolution of this field-from deep neural networks to graph-based structural modelling-highlighting the advantages of multi-task and multimodal learning strategies in identifying mechanism-related features. We further explore the emerging potential of generative models and causal inference methods for integrating permeability prediction with mechanism-aware drug design. Nowadays, ML-based BBB crossing prediction is in the critical transition from mere discriminative classification toward structure-function modelling from a mechanistic perspective. This paradigm shift provides a methodological progression and future roadmap for the integration of AI into neuropharmacological development.