a Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy , Chiang Mai University , Chiang Mai , Thailand.
b Computational Simulation and Modelling Laboratory (CSML), Department of Chemistry, Faculty of Science , Chiang Mai University , Chiang Mai , Thailand.
Toxicol Mech Methods. 2018 Jan;28(1):1-11. doi: 10.1080/15376516.2017.1351506. Epub 2017 Jul 25.
Inhibition of P-glycoprotein (P-gp)'s function may conduct significant changes in the prescription drugs' pharmacokinetic profiles and escalate potential risks in taking place of drug/herb-drug interactions. Computational modeling was advanced to scrutinize some bioflavonoids which play roles in herb-drug interactions as P-gp inhibitors utilizing molecular docking and pharmacophore analyses. Twenty-five flavonoids were utilized as ligands for the modeling. The mouse P-gp (code: 4Q9H) was acquired from the PDB. The docking was operated utilizing AutoDock version 4.2.6 (Scripps Research Institute, La Jolla, CA) against the NBD2 of 4Q9H. The result illustrated the high correlation between the docking scores and observed activities of the flavonoids and the putative binding site of these flavonoids was proposed and compared with the site for ATP. To evaluate hotspot amino acid residues within the NBD2, Binding modes for the ligands were achieved using LigandScout to originate the NBD2-flavonoid pharmacophore models. The results asserted that these inhibitors competed with ATP for binding site in the NBD2 (as competitive inhibitors) including the hotspot residues which associated with electrostatic and van der Waals interactions with the flavonoids. In MD simulation of eight delegated complexes selected from the analyzed flavonoid subclasses, RMSD analysis of the trajectories indicated the residues were stable throughout the duration of simulations.
抑制 P 糖蛋白（P-gp）的功能可能会导致处方药的药代动力学特征发生重大变化，并增加发生药物/草药药物相互作用的潜在风险。利用分子对接和药效团分析，对一些在草药药物相互作用中起作用的生物类黄酮作为 P-gp 抑制剂进行了计算建模研究。选用了 25 种类黄酮作为模型的配体。从 PDB 中获取了小鼠 P-gp（代码：4Q9H）。利用 AutoDock 版本 4.2.6（加利福尼亚州拉霍亚的斯克里普斯研究所）对 4Q9H 的 NBD2 进行对接。结果表明，对接评分与黄酮类化合物的观察活性之间具有高度相关性，并提出了这些黄酮类化合物的假定结合位点，并与 ATP 的结合位点进行了比较。为了评估 NBD2 内的热点氨基酸残基，使用 LigandScout 为配体获得了结合模式，以生成 NBD2-黄酮类药效团模型。结果表明，这些抑制剂与 ATP 竞争 NBD2 结合位点（作为竞争性抑制剂），包括与黄酮类化合物发生静电和范德华相互作用的热点残基。在所分析的黄酮类亚类中选择的八个指定复合物的 MD 模拟中，轨迹的 RMSD 分析表明，在整个模拟过程中，残基是稳定的。
