N-取代氟乙酰胺结构与急性毒性的CoMFA和CoMSIA研究

采用比较分子场分析(Co MFA)法和比较分子相似性分析(Co MSIA)法,对19种N-取代氟乙酰胺的小鼠急性毒性进行三维定量结构活性关系(3D-QSAR)的研究,模拟计算不同基团在立体场和静电场中对化合物急性毒性的影响,采用交叉验证相关系数(Q2)、非交叉验证相关系数(R2)表征模型的优劣。结果表明,Co MFA模型的交叉验证系数Q2为0.563,非交叉验证系数R2为0.992,优于二维构效关系,且其急性毒性主要由其立体场决定;单独采用立体场的Co MSIA模型预测能力最强,交叉验证系数Q2为0.767。在不同场组合的Co MSIA模型中,立体场和疏水场的贡献最大,而静电场的贡献最小。

CoMFA and CoMSIA Studies of N-substitued Fluoroacetamide Structures with Acute Toxicity

Using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out to calculate the in vivo acute toxicity toward rats of N-substituted fluoroacetamides based on the data of nineteen chemicals. The effects of different groups of steric and electrostatic field on the acute toxicity of fluoroacetamides were discussed in terms of cross validation correlation coefficient (Q²) and non-cross validated correlation coefficient (R²), which were introduced as the characterization of the model efficiency. Results show that the best CoMFA model included electrostatic and steric fields with the cross-validate regress coefficient Q² of 0.563 and noncross-validate regress coefficient R² of 0.992 is better than two-dimensional quantitative structure-activity relationship. The acute toxicity is mainly determined by steric field. On the other hand, CoMSIA analysis while only includes steric field is better than CoMFA model with the best result of Q2=0.767. Steric and hydrophobic fields contribute the most to CoMSIA prediction, while electrostatic field contributes the least.