新烟碱类化合物药效构象的分子对接研究

从烟碱型乙酰胆碱受体(nACHR)-烟碱(nicotine)复合体晶体模型出发, 采用SYBYL 6.92软件包中FlexX分子对接模块对新烟碱类化合物的3种已上市化合物吡虫啉、噻虫啉、烯啶虫胺和3种吡虫啉的结构衍生物同受体蛋白作用的精确模型进行了研究. 通过全局搜索方法构建配体的构象库进行对接, 依据构象间RMS值对结果进行分类结合CScore打分函数数据对对接结果进行筛选, 最终给出合理的新烟碱类化合物-烟碱型乙酰胆碱受体的药效作用构象模型: 配体吡啶环上氮原子通过水分子同受体Leu102, Met114形成氢键并且咪唑环或噻唑环上亲水侧链同受体CYS187或SER186形成氢键, 疏水侧链同疏水部位A (TYR164, TRP53, TYR89以及TYR185残基), 或疏水部位B (TYR132, CYS187和CYS188)相互作用. 此模型同早先有关文献报道的试验结果部分吻合, 充分表明了其合理性. 同时依据本构象模型, 在新烟碱类化合物结构方面提出了一些改良建议并为研究其高选择性指出方向.

Molecular Docking Study of Pharmacophoric Conformation of Neonicotinoids

Starting with the nicotine-nicotinic acetylcholine receptor (nACHR) complex crystal structure,the precise model for three kinds of neonicotinoids: imidacloprid,thiacloprid and nitenpyram and also three imidacloprid derivatives acting with the receptor protein was investigated by the FlexX molecular docking model of the SYBYL 6.92 software package. The conformation library constructed by a system search method was used in docking. The results were filtered according to the clustering by comparing the RMS of the conformations and the data of CScore evaluation function. Finally an appropriate neonicotinoid-nACHR pharmacophoric conformation model was given in which the nitrogen in the pyridine ring of a ligand gener-ates a hydrogen bond with the LEU102,MET114 residues in a receptor through a water molecule and the hydrophilic side chain on the imidazole or thiazole ring of the ligand generates a hydrogen bond with the CYS187 or SER186 residues in the receptor and also the hydrophobic side chain acts with the hydrophobic pocket A (TYR164,TRP53,TYR89 and TYR185) or the other hydrophobic pocket B (TYR132,CYS187 and CYS188). This model consists with the experiment result in the earlier reference so that the validity is strongly proved. According to the conformation model some suggestions about how the structures can be modified to improve the activity and some clues to the reason for their high selectivity were also given.