Designing modified polybrominated diphenyl ether BDE-47, BDE-99, BDE-100, BDE-183, and BDE-209 molecules with decreased estrogenic activities using 3D-QSAR, pharmacophore models coupled with resolution V of the 210-3 fractional factorial design and molecular docking

A 3D-QSAR model was constructed to predict polybrominated diphenyl ether (PBDE) estrogenic activities expressed as median effective concentrations (pEC(50)), and resolution V of the 2(10-3) fractional factorial design and a pharmacophore model were used to modify the target PBDE molecules BDE-47, BDE-99, BDE-100, BDE-183, and BDE-209 to decrease the estrogenic activities. The persistent-organic-pollutant-related and flame-retardant properties of the modified molecules were evaluated. The mechanisms involved in decreasing PBDE estrogenic activities were explored through molecular docking. The 3D-QSAR model gave a cross-validated correlation coefficient (q(2)) of 0.682 (i.e., > 0.5) and a non-cross-validated correlation coefficient (r(2)) of 0.980 (i.e., > 0.9). Mono- and di-substitutions and hydrophobic substituent groups gave 40 modified molecules with decreased estrogenic activities, including modified BDE-47 and BDE-99 with pEC50 decreased by > 10% and modified BDE-100, BDE-183, and BDE-209 with pEC50 decreased by > 20%. The modified molecules had similar flame-retardancy to the unmodified molecules, and lower biotoxicities (by a maximum of 17.27%), persistences (by a maximum of 55.68%), bioconcentration (by 4.28%-23.91%), and long-range transport potentials (by 0.72%-18.47%). Docking indicated that hydrophobic interactions were the main factors affecting PBDE estrogenic activities. The results provide a theoretical basis for designing less estrogenic flame retardants than are currently available.