Molecular Design of Environment-Friendly PAE Derivatives Based on 3D-QSAR Assisted with a Comprehensive Evaluation Method Combining Toxicity and Estrogen Activities

In this paper, a phthalic acid ester (PAE) three-dimensional quantitative structure-activity relationship (3D-QSAR) model with a double activity (toxicity and estrogenic activities) combination was established using a comprehensive evaluation method, in which the database of the combined activities consisted of 17 and 13 employed in the training sets and test sets, respectively. Ditridecyl phthalate (DTDP) derivatives with low-toxicity and estrogen combined activities were designed with DTDP as the target molecule. Four environmentally friendly DTDP derivatives were screened out by evaluating their environmental friendliness (expressed by persistence, bioaccumulation and migration) and practicability (expressed by insulation). Through the toxicity and estrogen single-activity model validation and contour map analyses, the results showed that the 3D-QSAR model for PAE toxicity and estrogen combined activities was feasible and the weight setting was reasonable. In addition, the mechanism analysis showed that the toxicity and estrogen combined activities of the four DTDP derivatives (2-CH3-DTDP, 2-OCHO-DTDP, 2-CH2COOH-DTDP, 2-CH2OH-DTDP) decreased in turn and were consistent with the single-activity model prediction. Meanwhile, it was speculated that the binding effect of the DTDP derivative molecules and estrogen-related proteins might be related to their hydrophobic interaction.