Dynamic-GLEP: a dynamics-informed deep learning framework for ligand efficacy prediction in representative Class A GPCRs.

Abstract

G protein-coupled receptors (GPCRs) represent the largest membrane protein family and remain central targets in drug discovery. Ligand efficacy reflects the ability to modulate receptor conformational states and extends beyond binding affinity to underpin functional selectivity. However, most computational approaches still emphasize affinity prediction, with limited capacity to capture the conformational dynamics driving efficacy. Here, we introduce Dynamic-GLEP, a structure- and mechanism-aware framework that integrates molecular dynamics (MD)-derived conformational ensembles with transfer learning on equivariant graph neural networks. By constructing multi-conformation receptor-ligand complexes and fine-tuning the EquiScore model, Dynamic-GLEP identifies conformation-dependent interaction features to distinguish agonists from nonagonists. Applied to the 5-HT1A receptor, the framework achieved an area under the curve (AUC) of 0.74 in cross-validation and 0.71 on an external Food and Drug Administration (FDA)-related dataset. Comparative analyses showed that Holo-based models are advantageous for scaffold optimization, whereas Apo-derived ensembles provided greater adaptability to chemically diverse ligands. Furthermore, extension to the adenosine A2A receptor yielded high performance (AUC > 0.85), underscoring the method's robustness and transferability under data-scarce conditions. Collectively, these results highlight Dynamic-GLEP as a reliable and interpretable platform for ligand efficacy prediction in Class A GPCRs, with broad potential to support virtual screening, candidate prioritization, and mechanism-driven drug design.