Multireceptor Structural Fingerprints of Fragrance‐Associated Phthalates and Their Metabolites: A Computational Perspective on Fragrance Safety

ABSTRACT Fragrance‐associated phthalates and their metabolites are relevant to the safety assessment of fragranced consumer products because dermal exposure may coexist with molecular interactions involving endocrine and xenobiotic‐responsive receptors. This study developed a low‐cost multireceptor computational framework to compare ten parent phthalates and metabolites across human oestrogen receptor alpha (ESR1), oestrogen receptor beta (ESR2), androgen receptor (AR), peroxisome proliferator‐activated receptor gamma (PPARγ), and pregnane X receptor (PXR). The workflow integrated physicochemical descriptors, crystallographic redocking, triplicate AutoDock Vina simulations, binding‐site residue fingerprints, and overlap with reference‐ligand contact environments. ESR1, ESR2, and AR showed robust top‐ranked redocking, whereas PPARγ and PXR recovered near‐native conformations that were not top‐ranked and were therefore interpreted more cautiously. Across the validated receptors, the compounds displayed receptor‐specific structural profiles rather than a single universal affinity hierarchy. Benzyl butyl phthalate (BBP) consistently showed strong compatibility, including the most favourable AR docking profile and 93.8% overlap with the crystallographic testosterone contact environment, while DEHP, MEHP, and MEOHP exhibited distinct receptor‐dependent patterns. These results define a comparative structural prioritization framework for fragrance‐safety research and identify compounds that warrant targeted experimental evaluation, without equating docking compatibility with endocrine activity or toxicity.