Organophosphate flame retardants (OPFRs) have caused widespread concern because of the harm to the environment. In this study, to better explain the mechanism for the binding of OPFRs with the tumor suppressor gene p53, an integrated experimental and in silico approach was used. The binding constants of 10 OPFRs were measured by surface plasmon resonance technology (SPR). The effect of OPFRs on p53 gene and protein expression in ZF4 cells was determined by quantitative real-time PCR and Western blotting. Molecular docking and dynamics simulation were explored to find that the H-bonds and hydrophobic interactions were the dominant interaction between OPFRs and p53. On the basis of the observed interactions, proper molecular structural descriptors were used to build the quantitative structure–activity relationship (QSAR) model. The current QSAR model provided robustness, predictive ability, and mechanism interpretability. The applicability domain of the QSAR was discussed by the Williams plot. The results showed that H-bonds and electrostatic interaction governed the binding affinities between OPFRs and p53.

Quantitative structure-activity relationships (QSARs) were determined using partial least square (PLS) and support vector machine (SVM). The predicted values by the final QSAR models were in good agreement with the corresponding experimental values. Chemical estrogenic activities are related to atomic properties (atomic Sanderson electronegativities, van der Waals volumes and polarizabilities). Comparison of the results obtained from two models, the SVM method exhibited better overall performances. Besides, three PLS models were constructed for some specific families based on their chemical structures. These predictive models should be useful to rapidly identify potential estrogenic endocrine disrupting chemicals.