Exploring The Binding Mode Of Key Enzymes And Ligands In Major Diseases Based On Molecular Dynamics Simulation

At present,major diseases that seriously threaten human health include diabetes,cancer and so on.According to a report published by International Diabetes Federation(IDF)in 2019,1 in 11 people in the world are suffering from diabetes.Diabetes is one of the fastest growing health challenges of the 21 st century,with the number of adults living with diabetes having more than tripled over the past 20 years.IDF estimates that there will be 578 million adults with diabetes by 2030.Diabetes is mainly manifested as insulin resistance.Although the current lifelong replacement therapy of insulin has become one of the most effective clinical treatments to control the disease process and prevent complications,multi-target combination drugs are needed to control the development of disease.Cancer can occur in almost every part of the human body,and its distinctive feature is the abnormal growth or metastasis.Cancer is the leading cause of death worldwide,and nearly 10 million people died of cancer in 2020.With early diagnosis and proper treatment according to the condition,some of the most common types of cancer,such as breast cancer and colon cancer,can possibly be cured.In this article,molecular dynamics simulations are used to conduct in-depth research on the key enzymes(N-terminal Maltase-glucoamylase,human dipeptidylpeptidase and tyrosine phosphatase 1B)in the process of human metabolism,and explore the binding modes of ligands targeted each key enzyme.The specific research content is as follows:1.Targeting N-terminal human maltase-glucoamylase to unravel possible inhibitors using molecular docking,molecular dynamics simulations,and adaptive steered molecular dynamics simulations.Multiple drugs are used for the treatment of type 2 diabetes,including glucagon like peptide-1(GLP-1)receptor agonists,dipeptidyl peptidase IV(DPP-4)inhibitors,traditional sulfonylureas biguanides,glinides,thiazolidinediones,?-glucosidase inhibitors,and sodium glucose cotransporter 2(SGLT2)inhibitors.?-glucosidase inhibitors have been used to control postprandial glucose levels caused by type 2diabetes since 1990.?-glucosidases are rather crucial in human metabolic system and are principally found in families 13 and 31.Maltase-glucoamylase(MGAM)belongs to glycoside hydrolase family 31.The main function of MGAM is to digest terminal starch products left after the enzymatic action of ?-amylase,and thence MGAM becomes an efficient drug target for insulin resistance.In order to explore the conformational changes in the active pocket and unbinding pathway for Nt MGAM,molecular dynamics(MD)simulations and adaptive steered molecular dynamics(ASMD)simulations were performed for two Nt MGAM-inhibitors [de-O-sulfonated kotalanol(DSK)and acarbose] complexes.MD simulations indicated that DSK bound to Nt MGAM may influence two domains(Inserted loop 1 and Inserted loop 2)by interfering the spiralization of residue H497-L499.The flexibility of Inserted loop 1 and Inserted loop 2 can influence the volume of the active pocket of Nt MGAM,which can affect the binding progress for DSK to Nt MGAM.ASMD simulations showed that comparing to acarbose,DSK escaped from Nt MGAM easily with lower energy.Asp542 is an important residue on the bottleneck of active pocket of Nt MGAM,and could generate hydrogen bond with DSK continuously.Our theoretical results may provide some useful clues for designing new ?-glucosidase inhibitors to treat type 2 diabetes.2.Molecular dynamics simulations study of the interactions between human dipeptidyl-peptidase ? and two substrates.Human dipeptidyl peptidase ?(hDPP ?)is a zinc-dependent hydrolase with broad substrate specificity for the N-terminal of various small peptides.HDPP ? is involved in many physiological processes,such as nociception,hypertension and many forms of cancers.In this study,500 ns molecular dynamics simulations were performed on free hDPP ?,hDPP ?-angiotensin ?(DRVYIHPF,Ang ?)complex,and hDPP ?-IVYPW complex to explore different binding modes and conformational changes.Results showed that in the case of hDPP ?-Ang ? complex,subsite S1 is small and hydrophobic,which makes the substrate susceptible to attack by nucleophiles species.And thence,the structures of the most stable conformations of the three systems revealed that there was ?-helix generated in residues R421-K423 in hDPP ?-Ang ?,while in the hDPP ?-IVYPW complex,?-helix generated partly.The ordered domain at R421 to K423 near the mechanical hinge in hDPP ?Ang ? helps water molecule nucleophilic attack the substrate.Our results will provide a new clue to design new inhibitors for hDPP ?.3.Explore the binding mode of inhibitors targeting the catalytical site of human tyrosine phosphatase 1B.Human tyrosine phosphatase 1B(PTP1B),a hydrolase of phosphotyrosinecontaining protein,acts as a major negative regulator of insulin signaling pathways through dephosphorylation of the insulin receptor,and has become an outstanding target for diabetes and obesity.Studies have shown that bromophenol compounds have the effect of controlling blood sugar levels,and can also specifically inhibit PTP1 B which makes it another potential efficient drug targeting PTP1 B.In this study,300 ns molecular dynamics simulations were performed on three systems--free PTP1 B and two complexes of synthetic bromophenol compounds(compound 4 and compound 22,see page 81 in the main text)and PTP1 B protein.The results showed that compound 22 can interact with sites A,B,and D of the PTP1 B protein,and bind to sites A and D with tight hydrogen bonds.Compound 22 can make the residues at the substrate recognition site of PTP1 B protein fluctuate drastically,which may help maintain the “open” conformation of the protein catalytic site and can be beneficial to the binding of ligand and protein.MM-GBSA results showed that both the residue Tyr46 and Asp181,an important residue in catalytic steps,had significant contributions to the binding of compound 4 to PTP1 B,but they were not sufficient to improve the inhibitory efficiency of compound 4.This may provide new directions and ideas for the design of specific inhibitors targeting PTP1B in the future.