Department of Analytical Chemistry Medical University of Lodz, 90-151, Łódź, Muszyńskiego 1, Poland.
Chemosphere. 2023 Jul;329:138649. doi: 10.1016/j.chemosphere.2023.138649. Epub 2023 Apr 10.
Novel Quantitative Structure-Activity Relationship (QSAR) models of compounds' placenta (PL) permeability expressed as their log FM (fetus-to-mother blood concentration) values or binary PL1/0 (crossing/non-crossing) score were generated using a number of statistical tools: Multiple Linear Regression, Boosted Trees, Principal Component Analysis and Artificial Neural Networks, on the basis of molecular descriptors calculated by Mordred software and selected using Partial Least Squares (PLS) analysis. It was established that the most important predictor of both log FM and the binary PL1/0 score is Lipinski - a binary variable reflecting the compounds' ability to satisfy the criteria of drug-likeness according to the Lipinski's "Rule of 5". The quantitative (log FM) and qualitative (PL1/0) models of PL permeability were applied to 345 pesticides from different chemical families (triazines, carbamates, pyrethroids, organochlorine, organophosphorus and miscellaneous compounds). The ability of studied pesticides to cross the placenta was assessed; the basic physico-chemical parameters responsible for good or poor placenta transport of pesticides were identified and the relationships between the pesticides' PL permeability, blood-brain barrier (BBB) transfer and gastro-intestinal (GI) absorption were investigated. It was found (on the basis of logistic regression analysis) that the probability of a compound crossing the placenta (PL1) is inversely correlated with its lipophilicity and molar refractivity and positively correlated with the total count of oxygen and nitrogen atoms.
采用多种统计工具（多元线性回归、Boosted Trees、主成分分析和人工神经网络），基于 Mordred 软件计算的分子描述符并使用偏最小二乘法（PLS）分析进行选择，建立了化合物胎盘（PL）通透性的新型定量构效关系（QSAR）模型，以表示其 log FM（胎儿-母体血液浓度）值或二进制 PL1/0（穿越/不穿越）分数。结果表明，无论是 log FM 还是二进制 PL1/0 分数的最重要预测因子都是 Lipinski，这是一个二进制变量，反映了化合物根据 Lipinski 的“五规则”满足药物相似性标准的能力。PL 通透性的定量（log FM）和定性（PL1/0）模型应用于来自不同化学家族的 345 种农药（三嗪类、氨基甲酸酯类、拟除虫菊酯类、有机氯、有机磷和杂环化合物）。评估了研究农药穿越胎盘的能力；确定了导致良好或不良胎盘转运的基本物理化学参数，并研究了农药 PL 通透性、血脑屏障（BBB）转运和胃肠（GI）吸收之间的关系。基于逻辑回归分析发现，化合物穿越胎盘（PL1）的概率与脂溶性和摩尔折射率呈负相关，与氧和氮原子总数呈正相关。
