AbstractA joint approach combining free‐energy calculations and calcium‐imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular‐dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non‐agonists. This study constitutes a proof‐of‐principle for the computational deorphanization of olfactory receptors.