Three-dimensional quantitative structure-activity relationship analysis for human pregnane X Receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.
Three-dimensional quantitative structure-activity relationship analysis for human pregnane X Receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.
复制标题
人孕烷 X 受体的三维定量构效关系分析用于预测人肝细胞中 CYP3A4 的诱导：基于结构的比较分子场分析。
DOI：
10.1002/jps.24235
复制
发表时间：
2015
影响因子：
3.8
通讯作者：
Shuichi Hirono.
中科院分区：
文献类型：
--
作者：
Koichi Handa;Izumi Nakagome;Noriyuki Yamaotsu;Hiroaki Gouda;Shuichi Hirono.
孕烷X受体[PXR(NR1I2)]诱导外源代谢基因和转运蛋白基因的表达。在这项研究中，我们旨在建立一种计算方法，通过不同化合物激活PXR的能力来量化它们的酶诱导能力，以便在药物发现和开发中应用。为了达到这一目的，我们开发了一个基于比较分子场分析(CoMFA)的三维定量结构-活性关系(3D-QSAR)模型，用于预测酶诱导活性，基于计算机配基对接从分子动力学模拟的轨迹中采样的多个PXR蛋白质结构。分子力学-表示配体-蛋白质结合自由能的广义Born/表面积分数被计算为每个配体。结果表明，由CoMFA模型预测的化合物的酶诱导活性与实验值吻合较好。最后，我们得出结论，该3D-QSAR模型有可能高精度地预测新化合物的酶诱导活性，因此在药物发现过程的早期阶段具有很高的应用价值。
The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure–activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand–protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process.