Molecular Dynamics Simulation And Network Pharmacology To Study The Mode Of Action Of Alzheimer’s Disease-associated Proteins With Different Ligands

Alzheimer’s disease(AD),a common neurodegenerative disease,occurs mainly in the elderly and is subsequently a common cause of dementia.The early stages of the disease are characterized by a marked loss of memory,a gradual loss of the ability to take care of oneself,psychiatric symptoms and movement disorders,and a progressive deterioration of the disease.Within today’s research,few drugs that can prevent and treat Alzheimer’s disease.Many drugs are not marketed because their safety has yet to be in clinical trials.The scientific community is now studying the development of new medications mainly through experimental techniques combined with computer-aided drug design,a process accelerated by bioinformatics tools.With the development of high-performance computers,molecular dynamics simulations can now handle complex biological macromolecular systems and physiological processes and occupy a unique advantage in protein structure-function studies.Network pharmacology achieves the goal of screening potential targets and core targets,biological functions and strategies,and molecular pathways for drug treatment of diseases by using a large amount of data in existing databases.Computer-aided drug design methods are used to discover the active ingredients of a large class of drugs and their related mechanisms affecting diseases,which can effectively stop the development of diseases,providing new means and ideas for drug development and treatment.This paper uses molecular dynamics simulations combined with network pharmacology techniques to study the mode of action of Alzheimer’s disease-associated proteins with different ligands.1.Molecular Dynamics Simulations to Explore the Binding Mode between the Amyloid-β protein Precursor(APP)and Adaptor Protein Mint2Alzheimer’s Disease(AD)is a chronic degenerative disease.However,few drugs can prevent and treat Alzheimer’s disease worldwide.The amyloid-β(Aβ)protein precursor(APP)plays a crucial role in the pathogenesis of Alzheimer’s disease(AD).The molecular recognition between APP and adaptor protein Mint2 has previously been addressed.But,the molecular mechanism of Mints’ dynamic regulation of APP binding remains elusive.In this study,four systems(free Mint2,Mint2-APP,mutant Mint2 free,mutant Mint2-APP)were performed with 400 ns molecular dynamics simulations.Our results indicated that residues S55 – K65 undergo secondary structural changes and form α helix after binding to APP during400 ns MD simulations.APP and the mutant Mint2 formed fewer hydrogen bonds in the process of binding,and the tight binding may be due to hydrophobic forces.Compared to WT Mint2,the active pocket of the mutant Mint2 becomes smaller,which is helpful for APP binding to the enzyme.Our results may provide valuable clues to designing new inhibitors for Mints.They are probing the Mechanisms of Inhibitors.2.Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulationsγ-secretase is an intramembrane proteolytic enzyme mainly involved in the cleavage and hydrolysis of amyloid precursor(APP).The catalytic subunit presenilin1(PS1)is the catalytic subunit of γ-secretase.Since it was found that PS1 was responsible for Aβ-producing proteolytic activity,which is involved in Alzheimer’s disease,it is believed that reducing the activity of PS1 and preventing or delaying the production of Aβ could help treat Alzheimer’s disease.Thus,in recent years,researchers have started investigating the potential clinical efficacy of PS1 inhibitors.Currently,most PS1 inhibitors are only used to study the structure and function of PS1,and a select few with high selectivity have been tested in clinics.Archaeal presenilin homolog(PSH)is a surrogate protease of presenilin useful for agent screening.In this study,we performed 200 ns molecular dynamics simulations(MD)of four systems to explore the conformational changes of different ligands binding to PSH.Our results indicated that the PSH-L679 complex formed 3-10 helices in TM4,loosened up TM4,and facilitated the entrance of substrates into the catalytic pocket.Additionally,we found that III-31-C contained an alpha helix that was more rigid to prevent the substrate from entering the active pocket.The inhibitor III-31-C has a stronger inhibitory effect than L679.Altogether,these results provide the basis for the potential design of newer PS1 inhibitors.3.Network Pharmacology to Reveal Action Mechanism of Green Tea Polyphenols Intervention in Alzheimer’s DiseaseThe accumulation of cross-β-sheet amyloid fibrils is a hallmark of the neurodegenerative process of Alzheimer’s disease(AD).Although it was reported that green tea contains substances such as epicatechin(EC),epicatechin-3-gallate(ECG),epigallocatechin(EGC),and epigallocatechin-3-gallate(EGCG)could alleviate the symptoms of AD and other neurodegenerative diseases,their pharmacological mechanism remains largely unexplored.This study used a computer-aided screening strategy to reveal the underlying mechanism of EC,ECG,EGC,and EGCG in AD.Our findings suggest that four tea polyphenols exert anti-AD effects through calcium signalling channels,neurodegeneration-multiple disease signalling pathways and other signalling channels.We also identified the critical residues of interaction between VEGFA and the four active components,which included Glu64 and Phe36.Altogether,we provided valuable insights into the molecular mechanism of tea polyphenols that could be used as a reference to improve therapeutic strategies against AD.