乙酰胆碱酯酶与新型香豆素类二聚体抑制剂的作用研究

Theoretical Studies on the Interactions of Acetylcholinesterase and Newly Coumarin Dimmers Inhibitors

本文通过分子对接的方法研究了香豆素类二聚体作为AChE抑制剂在正常活性位点(Ser203、Glu334和His447)和外周阴离子活性位点(His287、Tyr72、Tyr441和Glu292)的作用情况.研究结果表明,此类抑制剂有两个负电性中心:抑制剂母体的内酯区和6位或7位的苄基区.由于这两部分负电作用比较强极易与周围蛋白质发生静电作用,从而导致氢键的形成.研究发现香豆素二聚体类抑制剂更容易结合在AChE的外周阴离子活性区域.这类抑制剂在外周阴离子活性位点有相同的作用模式.这使得香豆素类二聚体有可能成为一种有更好应用前景的乙酰胆碱酯酶抑制剂.

Alzheimerg disease （AD） is a common age - related cognitive dysfunction in neurodegenerative diseases. So far, the drug that used to treat the diseases of AD is based on the acetylcholinesterase （ACHE） inhibitors. In this study, we study the interactions of the AChE with newly coumarin dimmer inhibitors in the regular active site （formed by residues Ser203, Glu334 and His447 ） ） as well as the outer peripheral anionic region （ surrounded by His287, Tyr72, Tyr441 and Glu292） using docking method. Two negative centers have been found on the lactone group or 6 - or 7 - positions of the benzyl group of these inhibi- tots. Studies show that the coumarin dimmer inhibitors are preferred to bind in the outer peripheral anionic region, all of which have similar binding modes. This makes coumarin dimmer inhibitors become a kind of promising AChE inhibitors.