Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis
Predicting blood-brain barrier partitioning of organic molecules using membrane-interaction QSAR analysis
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DOI：
10.1023/a:1020792909928
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发表时间：
2002-11-01
影响因子：
3.7
通讯作者：
Hopfinger, AJ
中科院分区：
文献类型：
--
作者：
Iyer, M;Mishra, R;Hopfinger, AJ
目的.膜相互作用定量构效关系（QSAR）分析（MI-QSAR）已被用于开发预测模型的血脑屏障分配的有机化合物，部分模拟的相互作用的有机化合物与磷脂丰富的区域的细胞膜。一个训练集的56个结构不同的化合物，其血脑屏障分配系数的测量被用来构建MI-QSAR模型。使用分子动力学模拟来确定每种测试化合物（溶质）与模型DMPC单层膜模型的明确相互作用。计算了一组额外的分子内溶质描述符，并在描述符的试验池中考虑用于构建MI-QSAR模型。采用多维线性回归拟合和遗传算法对QSAR模型进行优化。作为验证过程的一部分，使用MI-QSAR模型对7种化合物的测试集进行了评价。建立了血脑分配过程的MI-QSAR模型（R-2 = 0.845，Q（2）= 0.795）。发现血脑屏障分区取决于极性表面积、辛醇/水分配系数和化合物的构象灵活性以及它们与模型生物膜的“结合”强度。预测测试集化合物的血脑屏障分配措施具有与训练集化合物相同的准确性。的MI-QSAR模型表明，血脑屏障分区过程可以可靠地描述结构不同的分子提供的相互作用的分子与细胞膜的磷脂丰富的地区被明确考虑。
Purpose. Membrane-interaction quantitative structure-activity relationship (QSAR) analysis (MI-QSAR) has been used to develop predictive models of blood-brain barrier partitioning of organic compounds by, in part, simulating the interaction of an organic compound with the phospholipid-rich regions of cellular membranes.Method. A training set of 56 structurally diverse compounds whose blood-brain barrier partition coefficients were measured was used to construct MI-QSAR models. Molecular dynamics simulations were used to determine the explicit interaction of each test compound (solute) with a model DMPC monolayer membrane model. An additional set of intramolecular solute descriptors were computed and considered in the trial pool of descriptors for building MI-QSAR models. The QSAR models were optimized using multidimensional linear regression fitting and a genetic algorithm. A test set of seven compounds was evaluated using the MI-QSAR models as part of a validation process.Results. Significant MI-QSAR models (R-2 = 0.845, Q(2) = 0.795) of the blood-brain partitioning process were constructed. Blood-brain barrier partitioning is found to depend upon the polar surface area, the octanol/water partition coefficient, and the conformational flexibility of the compounds as well as the strength of their "binding" to the model biologic membrane. The blood-brain barrier partitioning measures of the test set compounds were predicted with the same accuracy as the compounds of the training set.Conclusion. The MI-QSAR models indicate that the blood-brain barrier partitioning process can be reliably described for structurally diverse molecules provided interactions of the molecule with the phospholipids-rich regions of cellular membranes are explicitly considered.