CycDelta: Multimodal Residue-Graph Learning of Permeability Changes in Cyclic Peptides
En palabras de los autores
Membrane permeability remains a major challenge in cyclic-peptide drug discovery, where optimization often depends on estimating changes relative to measured reference compounds. Existing predictors mainly model absolute permeability, while heterogeneity across literature sources complicates pooled training and comparative evaluation. We present CycDelta, a multimodal residue-graph model trained directly on within-source permeability differences. CycDelta combines directed message passing with pretrained Uni-Mol monomer embeddings, physicochemical descriptors and assay information in a shared encoder for reference and query peptides. To evaluate this comparative formulation under controlled conditions, we establish CycDeltaBench, comprising in-distribution, scaffold-based out-of-distribution, external and zero-shot unseen-assay tests. On the out-of-distribution task, CycDelta achieved Pearson 0.69 versus 0.46 for the strongest baseline. It also led all evaluated methods on two external data sets and achieved zero-shot Spearman 0.70 versus 0.32 for the strongest baseline on an unseen assay. Residue-level attribution relates predictions to monomer contributions, while gradient-guided screening supports prioritization of permeability-enhancing analogue hypotheses. These results position CycDelta as a transferable and interpretable framework for comparative permeability prediction and cyclic-peptide optimization.
Apareció: viernes, 25 de septiembre. bioRxiv. Preprint, todavía sin revisión por pares.