GPCR Ligand Bioactivity Prediction with Physics-Informed Dual-State Query Learning

Abstract: Predicting the bioactivity profiles of small molecules against G protein-coupled receptors (GPCRs) is a challenge in drug discovery. Although deep learning has accelerated the prediction of binding affinities, existing approaches often struggle to distinguish between functional efficacies because they neglect dynamic conformational equilibria. Furthermore, structure-based methods are frequently limited by the scarcity of high-resolution active-state crystal structures and the indistinguishability of conformational states in static representations. To bridge the gap between black-box prediction and biophysical reality, we propose Dual-State Query (DSQ), a physics-informed multimodal architecture that explicitly embeds the Monod-Wyman-Changeux (MWC) model of allostery within a neural network. Unlike conventional models that rely on explicit 3D structures, DSQ utilizes learnable orthogonal queries to extract disentangled representations of active and inactive receptor states. These latent representations are governed by a novel neural MWC gating module, which mathematically derives the probability of receptor activation from thermodynamic competition between ligand-state affinities and the receptor's intrinsic conformational energy barrier. A contrastive ranking objective is also introduced to enforce differential affinity constraints, ensuring physical consistency. Extensive experiments demonstrate that DSQ outperforms other baselines, particularly for the agonist subset. Additional homology-stratified, temperature-sensitivity, perturbation, clustering, and efficiency analyses show that DSQ provides useful thermodynamic inductive bias, while also exposing a clear limitation on low-homology receptors. The code is available at https://github.com/jiankliu/DSQ.