Molecular Modification of Benzophenone Derivatives for Lower Bioenrichment and Toxicity Through the Pharmacophore Model

Abstract

In this study, we used the improved extreme-difference normalization method to calculate the comprehensive evaluation values of bioenrichment and toxicity of benzophenone UV light absorbers(BPs). Based on this parameter, a 3D-QSAR(QSAR=quantitative structure activity relationship) pharmacophore model was constructed using Discovery Studio software and applied to the molecular modification of BPs. With three commonly used ingredients in sunscreen 2-hydroxy-4-methoxybenzophenone(BP-3), 2,2′-dihydroxy-4,4′-dimethoxybenzophenone(BP-6) and 2,2′-dihydroxy-4-methoxybenzophenone(BP-8) as target molecules, we performed BPs substitution reaction based on the binding positions of characteristic elements of the pharmacophore model and designed BP derivatives with reduced bioenrichment and toxicity. Stability and function evaluation showed that while the stability of 6 BP derivatives was enhanced, the light absorption capacity was also significantly enhanced(from 9.16% to 43.16%). Molecular dynamics simulation results showed that the binding ability of BP-609 molecule with serum albumin was reduced by 16.37% compared with BP-6, and the binding with collagen could not occur spontaneously, which could be used as an explanation for the simultaneous reduction of its bioenrichment and toxicity. Besides, through the simulation of human metabolism, it was found that the liver metabolites of BP-609 were less toxic, which reduced the potential risk of human metabolism. It proved that the molecular modification scheme of BPs was environment-friendly.

Keywords

Benzophenone type UV absorber / Bioenrichment / Toxicity / Comprehensive effect evaluation model / Molecular modification

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