EGCG Derivatives As AChE And MAO Inhibitors By Experimental And Molecular Modeling Study

Alzheimer'sandParkinson'sdiseasesaretwoimportanttypesof neurodegenerative disease.Acetylcholinesterase?AChE?and monoamine oxidase?MAO?are important targets for the treatment of Alzheimer's and Parkinson's diseases.Currently,the drugs which are used to treat the two diseases are mainly the acetylcholinesterase inhibitors and monoamine oxidase inhibitors.Epicatechin gallate?EGCG?is the most abundant catechin compound in tea.It has many physiological functions such as anti-tumor,anti-oxidation,anti-virus and anti-radiation.A series of structural derivatives of EGCG have improved the drawbacks of EGCG itself,such as poor lipid solubility,low bioavailability,and instability.Thus,the article embarks from the EGCG derivatives to screening AChE and MAO inhibitors,and use the method of molecular dynamics simulation to study the mechanism of inhibitors to AChE and MAO.The experimental results will provide a new way to reasonable design AChE and MAO inhibitors.The first chapter summarizes the structure,active site and catalytic mechanism of acetylcholinesterase,as well as the inhibitors of AChE.We summarized the research progress of monoamine oxidase and the inhibitors of MAO and the biological activity of EGCG.We use experimental and molecular simulation method to study the inhibitory activity of EGCG analogues to AChE and MAO and its interaction mechanism.In the second chapter,the method of Ellman is used to study the inhibitory activity of 85 EGCG derivatives to AChE.The results show that there are three compounds,2159-3796,0908-0110,0110-0908 have high inhibitory activity,half inhibitory concentration(IC₅₀)were 7.89?M and 30.13?M and 74.6?M.The method of microcalorimetry?MST?is used to study the affinity constant Kd value of the most active compound to AChE.The Kd value of 2159-3796 to AChE is 80.33?M.Then,we use the method of molecular dynamics simulation to study the activity differences between 2159-3796 and Huperzine A.Molecular dynamics simulation results show that the head of hupA carbonyl oxygen atoms with AChE Ser200,Ala201,Gly118,Gly119 formation of stable hydrogen bond network to inhibit the activity of AChE.In the combination of 2159-3796 and AChE models because the steric hindrance effect2159-3796 cannot form hydrogen bond network with Ser200,Ala201,Gly118 and Gly119.The reason determines the activity differences of two compounds.This provides evidence for design of the inhibitors of AChE.In the third chapter,we use Holt method to screen the inhibitory activity of 85EGCG derivatives to MAO.The results show that there are four compounds of8019-8452,8005-6325,8018-9337 and 8018-5599,which have high inhibition activity on MAO.All four IC₅₀0 values are below 100?M.Additionally we use the Holt method to study the selectivity of the four compounds for MAO-A and MAO-B.The results shows that 8019-8452 has higher selectivity of MAO-B and other three molecules have higher selectivity of MAO-A.Then,we used molecular dynamics simulation to study the mechanism of the inhibition and selectivity mechanism of the four compounds of 8019-8452,8005-6325,8018-9337 and 8018-5599 for MAO.The results show that Gln215 is the key residual basis for the selective inhibition of MAO-A and the auxiliary factor FAD is the selective key residue of MAO-B.The molecules are more flexible and easy to interact with FAD,which tends to be more selective in inhibiting MAO-B.The methyl benzoate skeleton is a structure that inhibits MAO and has high selectivity to MAO-A.These experimental results provide theoretical basis for the rational design of higher selective MAO inhibitors.The experimental result of the experiment by means of biological experiment methods combined with molecular dynamics simulation method to explore inhibitory activity to EGCG derivatives of AChE and MAO and the interaction mechanism.The results will help us to discover AChE and MAO inhibitors and help us discovery the biological activity of EGCG derivatives.