Quality Control of Coumarins, Furocoumarins and Polymethoxyflavones in Citrus Essential Oils: In Silico Analysis

Citrus essential oils (EOs) contain a variety of secondary metabolites, including coumarins (Cs), furocoumarins (FCs) and polymethoxyflavones (PMFs), all with different biological activities. While Regulation (EC) No 1334/2008 strictly regulates the use of coumarins, undesirable side effects of consuming furocoumarins remain without established maximum toxicity limits for human dietary intake. This study is based on an in‐silico approach aimed at determining these toxicity limits for the oxygenated heterocyclic compounds of citrus EOs approved for use in food. In addition, an innovative quantitative structure‐property relationship (QSPR) using the linear retention index system was explored to characterize the oxygenated heterocyclic compounds (COHs) present in these essential oils. Molecular docking of the studied compounds provided crucial insights into the structure‐odor relationships, offering insights into their mechanisms of action. In addition, an analysis of the pharmacokinetic and pharmacodynamic properties through ADME‐Tox deconstruction provides insight into the potential side effects of their consumption. The results are consolidated by dynamic simulations, providing crucial data for the development of regulations on the maximum toxicity limits of citrus EOs, given the health implications of the various compounds such as coumarins, furocoumarins and polymethoxyflavones present in these essential oils. The study explores olfaction, from chemoreception to cognitive implications. Odorant molecules (X1, X2, X4) derived from 5‐geranyloxy‐7‐methoxycoumarin show promise without a global charge that could affect dipoles. These molecules meet ADME‐Tox criteria and show stability in simulations with the porcine odor‐binding protein. However, practical applications in the flavor and fragrance industry are limited currently. These results may provide guidance to researchers in the field of olfaction.