GPCRact: a hierarchical framework for predicting ligand-induced GPCR activity via allosteric communication modeling

TL;DR

GPCRact is a new framework that accurately predicts how ligands affect GPCR activity by modeling allosteric communication, improving drug discovery.

Contribution

GPCRact introduces a hierarchical, structure-aware model that captures allosteric communication in GPCRs using biophysical principles.

Findings

GPCRact achieves state-of-the-art performance on predicting ligand-induced GPCR activity.

The model identifies biologically validated allosteric pathways, enhancing interpretability.

It outperforms existing models on allosterically complex receptors.

Abstract

Accurate prediction of ligand-induced activity for G-protein-coupled receptors (GPCRs) is a cornerstone of drug discovery, yet it is challenged by the need to model allosteric communication—the long-range signaling linking ligand binding to distal conformational changes. Prevailing sequence-based models often fail to capture these three-dimensional dynamics, a limitation frequently masked by averaged performance on simpler Class A targets. To address this, we introduce GPCRact, a novel framework that models the biophysical principles of allosteric modulation in GPCR activation. It first constructs a high-resolution, three-dimensional structure-aware graph from the heavy-atom coordinates of functionally critical residues at binding and allosteric sites. A dual attention architecture then captures the activation process: cross-attention encodes the initial ligand-protein interaction at the binding site, whereas self-attention learns the subsequent intra-protein signal propagation. This hierarchical architecture is built upon an E(n)-Equivariant Graph Neural Network (EGNN) to explicitly model conformational consequences of ligand binding, and is further refined with a tailored loss function and inference logic to mitigate error propagation. Underpinned by GPCRactDB, a comprehensive database we constructed for this study, GPCRact not only achieves state-of-the-art performance but also demonstrates robustly superior accuracy on a curated benchmark of allosterically complex receptors where existing models systematically underperform. Crucially, analysis of the learned attention weights confirms that the model identifies biologically validated allosteric pathways, offering a significant step toward resolving the black box nature of previous methods. Thus, GPCRact provides a more accurate, interpretable, and mechanistically-grounded solution to a long-standing challenge, paving the way for effective structure-guided drug discovery.

Graphical Abstract

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