An Interpretable, Thermodynamics-Based Deep Learning Framework for Predicting and Optimizing Drug Membrane Permeability

Cellular membranes serve as selective barriers, and membrane permeability is crucial for drug pharmacokinetics. While in vitro and in vivo methods exist, predicting and designing membrane permeability remains challenging. We developed a thermodynamics-based deep learning framework to analyze the structure-permeability relationship, based on the concept that interactions between membrane lipids and small molecules influence permeability. We determined the membrane penetration thermodynamics of 8,239 compounds using coarse-grained molecular dynamics simulations and created interpretable graph neural network models to predict and design drug membrane permeability. As a proof-of-concept, we designed a novel nasal-administered melatonin analog, MT-A2, optimized for permeability. Compared with melatonin, MT-A2 showed superior nasal absorption, prolonged brain retention, and enhanced sleep efficacy. Our results provide a promising approach for predicting and designing membrane permeability, aiding in the development of drugs with better pharmacokinetics.