基于CoMFA方法建立预测35种苯砜基羧酸酯衍生物对发光菌急性毒性的构效关系模型
Establishing a Structure-activity Relationship Model for Predicting Acute Toxicity of 35 Phenylsulfonyl Carboxylate Derivatives to Luminescent Bacteria by Using CoMFA Method
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摘要: 基于比较分子力场分析(CoMFA)方法建立35种苯砜基羧酸酯衍生物对发光菌急性毒性(-lgEC50)的三维定量构效关系(3D-QSAR)。训练集中30个化合物用于建立预测模型，测试集12个化合物(含模板分子1及新设计的6个分子)作为模型验证。已建立的3D-QSAR模型的交叉验证系数(R2cv)、非交叉验证系数(R2)分别为0.665、0.960，说明所建模型具有较强的稳定性和良好的预测能力。该模型中立体场、静电场贡献率依次为70.0%、30.0%，表明影响急性毒性(-lgEC50)的主要因素是取代基的疏水性和空间契合，其次是库仑力、氢键及配位。基于三维等势图，设计了6个对发光菌具有较高急性毒性的分子，有待生物学实验验证。Abstract: In this work, the comparative molecular field analysis (CoMFA) method was used to construct a three-dimensional quantitative structure-activity relationship (3D-QSAR) for the acute toxicity (-lgEC50) of 35 phenylsulfonyl carboxylate derivatives to luminescent bacteria. In the established model, 30 compounds were used as a training set to build the prediction model, and another 12 compounds (including 1 template molecule and 6 newly designed molecules) were used as a test set to verify the accuracy of the model. The established 3D-QSAR model showed good stability and predictive ability, with cross-validation coefficients (R2cv) of 0.665 and non-cross-validation coefficients (R2) of 0.960. Model analysis showed that the contribution rates of steric fields and electrostatic fields to acute toxicity were 70.0% and 30.0%, respectively, indicating that the hydrophobicity and spatial structure of substituents were the most important factors in determining acute toxicity, followed by charge distribution, hydrogen bonding, and coordination. Guided by the three-dimensional equipotential map, this paper designed 6 new molecules that were expected to have higher acute toxicity to luminescent bacteria. These molecules needed to be further verified for their activity through biological experiments. These findings provided not only a theoretical basis for understanding the toxicity mechanism of phenylsulfonyl carboxylate derivatives but also useful information for designing compounds with higher toxicity, which is of great significance for environmental monitoring and the development of biotechnology.
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