摘要
为了研究药物与胃蛋白酶(PEP)相互作用后对药效及胃部消化能力的影响,在模拟生理条件下,建立了光谱测定。本文通过荧光法、同步荧光法和分子对接模拟技术研究了在298,310,318K时盐酸吡格列酮(PGH)和PEP之间的相互作用机理。结果表明,PGH与PEP之间通过静电引力及氢键作用以静态猝灭的方式形成了1∶1的稳定复合物;PEP的酪氨酸残基(Tyr)和色氨酸残基(Trp)均参与了反应;PGH-PEP的结合对后继配体存在正协同作用。通过估算得知:当患者服用PGH15~45mg时,胃液中的药物结合率为0.0013%~0.0032%,数值很小,即PGH与PEP的结合对PGH药效几乎没有影响;PEP的结合率为69.76%~87.37%,即服用PGH使得游离的PEP减少69.76%~87.37%,表明服用PGH将使患者的消化功能受到影响。分子对接技术表明PGH与PEP的最佳结合位点位于PEP的催化活性中心处,且两者的结合作用改变了PEP催化活性中心处氨基酸残基的微环境。
In order to study the effect of the interaction between drugs and pepsin(PEP) on the pharmacodynamics and digestive ability of stomach,the spectral determination was established under simulated physiological conditions. At 298,310 and 318 K,the interaction mechanism between pioglitazone hydrochloride(PGH) and PEP was studied by fluorescence,synchronous fluorescence and molecular docking simulation. The results showed that a stable 1 ∶1 complex was formed between PGH and PEP by electrostatic force and hydrogen bonding in a static quenching manner. Tyrosine residues(Tyr) and tryptophan residues(Trp) in PEP were involved in the reaction. The binding of PGH-PEP had positive cooperativity effect on the subsequent ligands. The results showed that when patients took PGH 15-45 mg,the drug binding rate in gastric juice was 0.0013%-0.0032%,which was very small,that is,the combination of PGH and PEP had little effect on PGH. The binding rate of PEP was 69.76%-87.37%,that is,PGH reduced the free PEP by 69.76%-87.37%, indicating that PGH would affect the digestive function of the patients. Molecular docking technique showed that the best binding site between PGH and PEP was located at the catalytic active site of PEP,and the interaction between them changed the microenvironment of amino acid residues in PEP catalytic active center.
作者
王春丹
刘保生
边刚
马丽花
张红彩
程旭
WANG Chun-dan;LIU Bao-sheng;BIAN Gang;MA Li-hua;ZHANG Hong-cai;CHENG Xu(Key Laboratory of Analytical Science and Technology of Hebei Province,National Chemistry Experimental Teaching Demonstration Center Hebei University,Key Laboratory of Pharmaceutical Chemistry and Molecular Diagnosis Ministry of Education,Baoding 071002,China)
出处
《发光学报》
EI
CAS
CSCD
北大核心
2019年第7期922-929,共8页
Chinese Journal of Luminescence
基金
国家自然科学基金(21375032)资助项目~~
关键词
盐酸吡格列酮
胃蛋白酶
作用机理
荧光法
分子对接
pioglitazone hydrochloride
pepsin
interaction mechanism
fluorescence spectroscopy
molecular docking