Screening of benzophenone ultraviolet absorbers with high-efficiency light absorption capacity, low-permeability and low-toxicity by 3D-QSAR model

•Charge distribution affects the CVs of ultraviolet absorption, skin permeability, and planarian toxicity of BP molecules.•Excited state transition dipole moment affects the ultraviolet absorption capacity of BP molecules.•Decrease in the number of amino acids that form van der Waals interactions reduced the skin permeability.•Weakened strength and decrease in the number of hydrophobic interactions reduced the planarian toxicity. In this study, the synthetical index method was used to calculate the comprehensive effect value (CV) of ultraviolet (UV) absorption capacity, skin permeability, and planarian toxicity of benzophenone-type (BP) compounds. The comparative molecular similarity index analysis (CoMSIA) method with the CV and the molecular structure of BPs as the dependent and independent variables, respectively, was used to construct the BPs comprehensive effect three-dimensional quantitative structure activity relationship model. 2,4-dihydroxybenzophenone (BP-1) and 2-hydroxy-4-methoxybenzophenone (BP-3), which are widely used in sunscreens, were used as the target molecules to design novel BPs with high-efficiency light absorption capacity, low permeability, and low toxicity. A total of 30 novel derivative molecules with CV increased by >20% were designed. The practicality and functionality of the novel molecules were evaluated, six novel BPs with stronger UV absorption capacity (increase of 46.01%–277.57%), lower skin permeability (decreased by 50.46%–96.47%), and lower planarian toxicity (decreased by 82.20%–431.79%) were identified. Time-dependent density functional theory was used to analyse the electron excitation of BP molecules. The results revealed that the increased contribution rate of orbital transitions, changes in the main transition orbital pairs (MO pairs), changes in excited state transition dipole moments, and the difference in electron transfer characteristics between the ground state and the excited state enhanced the UV absorption capacity of BP molecules. The docking analysis results of BP molecules with human skin keratin and RNA helicase of Dugesia japonica revealed that the reduction of amino acids involved in van der Waals interaction was the primary cause of the decrease in skin permeability of BP molecules. The weakening of the hydrophobic interaction strength and the decrease of the number are the main reasons for the reduction of the planarian toxicity of BP molecules. Molecular dynamics simulation and binding energy cal