Deep learning reveals endogenous sterols as allosteric modulators of the GPCR-Gα interface.

ABSTRACT: Endogenous intracellular allosteric modulators of GPCRs remain largely unexplored, with limited binding and phenotype data available. This gap arises from the lack of robust computational methods for unbiased cavity identification, cavity-specific ligand design, synthesis, and validation across GPCR topology. Here, we developed Gcoupler, an AI-driven generalized computational toolkit that leverages an integrative approach combining de novo ligand design, statistical methods, Graph Neural Networks, and bioactivity-based ligand prioritization for rationally predicting high-affinity ligands. Using Gcoupler, we interrogated intracellular metabolites that target and regulate the GPCR-Gα interface (Ste2p-Gpa1p), affecting pheromone-induced programmed cell death in yeast. Our computational analys

SUBMITTER: Mohanty SK 

PROVIDER: S-EPMC12685305 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature