Martinčič R, Venko K, Župerl Š, Novič M
a Laboratory of Chemometrics , National Institute of Chemistry , Ljubljana , Slovenia.
SAR QSAR Environ Res. 2014;25(11):853-72. doi: 10.1080/1062936X.2014.962082. Epub 2014 Oct 22.
Membrane transport proteins are essential for cellular uptake of numerous salts, nutrients and drugs. Bilitranslocase is a transporter, specific for water-soluble organic anions, and is the only known carrier of nucleotides and nucleotide-like compounds. Experimental data of bilitranslocase ligand specificity for 120 compounds were used to construct classification models using counter-propagation artificial neural networks (CP-ANNs) and support vector machines (SVMs). A subset of active compounds with experimentally determined transport rates was used to build predictive QSAR models for estimation of transport rates of unknown compounds. Several modelling methods and techniques were applied, i.e. CP-ANN, genetic algorithm, self-organizing mapping and multiple linear regression method. The best predictions were achieved using CP-ANN coupled with a genetic algorithm, with the external validation parameter QV(2) of 0.96. The applicability domains of the models were defined to determine the chemical space in which reliable predictions can be obtained. The models were applied for the estimation of bilitranslocase transport activity for two sets of pharmaceutically interesting compounds, antioxidants and antiprions. We found that the relative planarity and a high potential for hydrogen bond formation are the common structural features of anticipated substrates of bilitranslocase. These features may serve as guidelines in the design of new pharmaceuticals transported by bilitranslocase.
膜转运蛋白对于细胞摄取多种盐、营养物质和药物至关重要。胆绿素转运蛋白是一种特异性转运水溶性有机阴离子的转运蛋白，是已知唯一的核苷酸及类核苷酸化合物载体。利用胆绿素转运蛋白对120种化合物的配体特异性实验数据，采用反向传播人工神经网络（CP-ANNs）和支持向量机（SVMs）构建分类模型。使用一组经实验测定转运速率的活性化合物子集构建预测性定量构效关系（QSAR）模型，以估算未知化合物的转运速率。应用了多种建模方法和技术，即CP-ANN、遗传算法、自组织映射和多元线性回归方法。使用结合遗传算法的CP-ANN实现了最佳预测，外部验证参数QV(2)为0.96。定义了模型的适用域，以确定能够获得可靠预测的化学空间。将模型应用于估算两组具有药学意义的化合物（抗氧化剂和抗朊病毒剂）的胆绿素转运蛋白转运活性。我们发现相对平面性和形成氢键的高潜力是胆绿素转运蛋白预期底物的共同结构特征。这些特征可作为设计由胆绿素转运蛋白转运的新型药物的指导原则。
