Gao Jing, Wu Xiao-Hui, Dong Wei-Li, Wang Shu-Qing
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Protein Pept Lett. 2013 Nov;20(11):1238-45. doi: 10.2174/09298665113209990044.
The crystal complex propofol/GLIC (the bacterial homologue from Gloeobacter violaceus) recently determined also showed sensitivity to general anesthetics, belonging to the pLGIC (pentameric ligand-gated ion channels) family as a homopentameric member, which are potentiated and inhibited by general anesthetics and mimic changes elicited by anesthetics in physiologic targets as ion channels, providing the useful information for general anesthetics and allosteric modulators design. Thirteen active compounds selected from the previous data sets are used as reference and seed structures for developing novel general anesthetics via the scoring function of lead optimization using pharmacophoric & shape similarity integrated in Muse™ molecular design workflow. Autodock4.0 is validated its accuracy by two computational procedures and used for docking calculations in this study. Finally, the top ten invented propofol analogs reported here exhibit more favorable binding energies geometric matching than propofol. Especially, the comp#1 fits the binding site well in geometric shape with the lowest binding energy than any other compounds, and makes the hydrophobic interaction with the binding site formed by M4 helixes and lipids of receptor as well. More importantly, the interactions between ligand and lipids caused by general-anesthetic binding would be specially considered in novel general anesthetic design. accordingly, the findings reported here may provide useful insights for discovering more effective general anesthetics.
最近确定的晶体复合物丙泊酚/GLIC（来自紫球藻的细菌同源物）也显示出对全身麻醉药敏感，作为同五聚体成员属于pLGIC（五聚体配体门控离子通道）家族，全身麻醉药可增强和抑制该家族，并且模拟麻醉药在离子通道等生理靶点中引起的变化，为全身麻醉药和变构调节剂设计提供了有用信息。从先前的数据集中选择的13种活性化合物用作参考和种子结构，通过在Muse™分子设计工作流程中集成的药效团和形状相似性的先导优化评分功能来开发新型全身麻醉药。通过两种计算程序验证了Autodock4.0的准确性，并将其用于本研究中的对接计算。最后，此处报道的十种最具创新性的丙泊酚类似物在几何匹配方面比丙泊酚表现出更有利的结合能。特别是，化合物1在几何形状上与结合位点匹配良好，结合能比任何其他化合物都低，并且还与由M4螺旋和受体脂质形成的结合位点发生疏水相互作用。更重要的是，在新型全身麻醉药设计中，将特别考虑全身麻醉药结合引起的配体与脂质之间的相互作用。因此，此处报道的研究结果可能为发现更有效的全身麻醉药提供有用的见解。
