Systematic benchmarking of 13 AI methods for predicting cyclic peptide membrane permeability.

Cyclic peptides are promising drug candidates due to their ability to modulate intracellular protein-protein interactions, a property often inaccessible to small molecules. However, their typically poor membrane permeability limits therapeutic applicability. Accurate computational prediction of permeability can accelerate the identification of cell-permeable candidates, reducing reliance on time-consuming and costly experimental screening. Although deep learning has shown potential in predicting molecular properties, its application in permeability prediction remains underexplored. A systematic evaluation of these models is important to assess current capabilities and guide future development. In this study, we conduct a comprehensive benchmark of 13 machine learning models for predicting cyclic peptide membrane permeability. These models cover four types of molecular representations: fingerprints, SMILES strings, molecular graphs, and 2D images. We use experimentally measured PAMPA permeability data from the CycPeptMPDB database, comprising nearly 6000 cyclic peptides, and evaluate performance across three prediction tasks: regression, binary classification, and soft-label classification. Two data-splitting strategies, random split and scaffold split, are used to assess the generalizability of trained models. Our results show that model performance depends strongly on molecular representation and model architecture. Graph-based models, particularly the Directed Message Passing Neural Network (DMPNN), consistently achieve top performance across tasks. Regression generally outperforms classification. Scaffold-based splitting, although intended to more rigorously assess generalization, yields substantially lower model generalizability compared to random splitting. Comparing prediction errors with experimental variability highlights the practical value of current models while also indicating room for further improvement.