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GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson’s disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi  et al . and Dvorak  et al . included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg  et al . and Liu  et al . have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca 2+  assay demonstrated that residues F109 3×33 , H187 5×43 , W241 6×48  and N271 7×38 , but not E108 3×32 , are highly important for the activation of GPR139 as predicted by the receptor model. The initial ligand-receptor complex was optimized through free energy perturbation simulations, generating a refined GPR139 model in agreement with experimental data. In summary, the GPR139 reference surrogate agonists 1a and 7c, and the endogenous amino acids  l -Trp and  l -Phe share a common binding site, as demonstrated by mutagenesis, ligand docking and free energy calculations.

The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site