Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common...

Distinct PAEs are implicated in breast cancer progression through multiple molecular pathways. This study aims to elucidate the potential mechanisms in common by which PAEs promote breast cancer progression. Dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), and diethylhexyl phthalate (DEHP) were selected as representative PAE compounds. Network toxicology guided the construction of a regulatory network centered on five key transcription factor-associated genes: TP53, CTNNB1, PPARA, ESR1, and CDKN2A. Differential expression and survival analyses confirmed the significant impact of these hub genes on breast cancer (p < 0.05). Molecular docking results revealed direct interactions between the three PAEs and hub targets, while BBP had the strongest PAE-hub gene interaction and DEHP had the weakest one. Computer-aided molecular design (CAMD), combined with molecular docking, found the importance of alkyl chains and phenyl in PAE-hub gene interaction. A group addition/subtraction controlled experiment revealed that the binding affinities of modified BBP variants to hub genes are all weaker than the unmodified parent. The drop was significant whether the C17 alkyl chain was lengthened to match DEHP (p = 0.026) or the phenyl group was removed (p = 0.022). The findings provide novel insights into the mechanism in common of PAE-promoting breast cancer and offer a foundation for the unified intervention strategies and the design of safer plasticizer alternatives.