Miyata Ken-Ichi, Nakagawa Yoshiaki, Kimura Yasuhisa, Ueda Kazumitsu, Akamatsu Miki
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Otsuka Pharmaceutical Co., Ltd, Tokushima 771-0182, Japan.
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Bioorg Med Chem. 2016 Jul 15;24(14):3184-91. doi: 10.1016/j.bmc.2016.05.039. Epub 2016 May 20.
We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation.
我们之前证明，二苯甲酰肼（DBHs）不仅是P-糖蛋白（P-gp）的底物，也是其抑制剂。在本研究中，我们评估了两个系列的DBHs对P-gp介导的奎尼丁转运的抑制作用，并进行了经典的定量构效关系（QSAR）分析和对接模拟，以研究P-gp底物/抑制剂识别的潜在机制。QSAR分析结果表明，疏水因素对抑制活性最为重要，而电子效应和空间效应也会影响活性。在每个系列中观察到的不同取代基效应表明了每个系列DBHs的不同结合模式，对接模拟结果支持了这一点。
