基于UFLC-MS/分子模拟计算的吴茱萸醇提取物中胆碱酯酶抑制剂筛选

Screening of Cholinesterase Inhibitors in Fructus Evodiae Alkaloids Based on UFLC-MS/molecular Simulation

采用超高速液相色谱⁃质谱(UFLC⁃MS)研究了吴茱萸醇提取物中入血小分子化合物的体内药代动力学过程.同时对UFLC⁃MS生物样品分析方法进行包括特异性、线性、精密度、准确度、稳定性、基质效应和回收率等考察,结果表明,该方法稳定可靠,且醇提取物中10个生物碱类化合物均被胃肠道快速吸收,并且多数化合物血药浓度在1~2 h左右达到峰值.将吸收入血的10个生物碱类化合物与乙酰胆碱酯酶和丁酰胆碱脂酶进行柔性分子对接及构效关系分析,发现其中活性最高的为去氢吴茱萸碱、吴茱萸碱、吴茱萸次碱和吴茱萸酰胺Ⅰ4个吲哚型生物碱,它们与乙酰胆碱酯酶的对接打分均在-46.02 kJ/mol以下;与丁酰胆碱脂酶对接打分均在-41.84 kJ/mol以下.吴茱萸碱、吴茱萸次碱、去氢吴茱萸碱和吴茱萸酰胺可能是以乙酰胆碱酯酶和丁酰胆碱脂酶为靶点的胆碱酯酶抑制剂前体化合物.

Cholinesterase inhibitors targeting acetylcholinesterase and butyryl cholinesterase were screened from alcohol extracts of evodia rutaecarni.The pharmacokinetic process of small molecule compounds in evodia evodia alcohol extract was studied by ultra fast liquid chromatography-mass spectrometry(UFLC-MS).At the same time,UFLC-MS analysis method included specificity,linearity,precision,accuracy,stability,the matrix effect and recovery projects such as a comprehensive inspection.The results show that the method is sta-ble and reliable,and 10 alkaloids compounds in alcohol extract can be absorbed quickly,gastrointestinal tract and the majority of compound blood drug concentration peak at about 1—2 h.Flexible molecular docking and structurally activity analysis of 10 alkaloid compounds with acetylcholinesterase and butylcholinesterase were conducted.It was found that the four compounds with the highest activity were indole-type alkaloids,namely evodiamine,rutaecarpine,dehydroevodiamine and wuchuyuamideⅠ,respectively.Their docking scores with acetylcholinesterase were all below-46.02 kJ/mol.The docking scores with butylcholinesterase were all below-41.84 kJ/mol.Evodiamine,rutaecarpine,dehydroevodiamine and wuchuyuamide may be precursor compounds of cholinesterase inhibitors targeting acetylcholinesterase and butyryl cholinesterase.