To Explore The Interactions Between Lysine Specific Demethylase 1 And Inhibitors Using Molecular Dynamics Simulations

Lysine-specific demethylase 1(LSD1)is a histone demethylase that exhibits dual functions of transcriptional repression and activation in epigenetic studies.Its abnormal function is associated with various pathological conditions.Extensive research data indicates that LSD1 is often highly expressed in hematologic malignancies and various solid tumors.LSD1 promotes cancer progression by influencing the tumor cell cycle through methylation and demethylation processes that facilitate tumor growth,invasion,and metastasis.Therefore,LSD1 is an important target for tumor therapy,LSD1 inhibitors have promising therapeutic potential for a variety of malignancies.Traditional experimental techniques can reveal the structural features of protein molecules,but they usually fail to show dynamic changes.This requires the use of molecular dynamics simulations,which simulate dynamic conformational changes in the binding of proteins to inhibitors at the atomic level,which is difficult to achieve with experimental methods.Therefore,molecular dynamics simulation has unique advantages and potential for the design and development of targeted drugs,which can demonstrate the microscopic structural and dynamic changes in time and space after the binding of target proteins to the designed drugs.This method is highly compatible with experimental data and fast in computation,and is a dynamic observation of the target system.By mastering the dynamic conformational changes of protein inhibitor binding,we can gain a deeper understanding of the intrinsic mechanism of action.In this paper,molecular dynamics simulations were used to investigate the dynamic conformational changes and interaction mechanisms of the LSD1-inhibitor complex system.Based on the comprehensive analysis of LSD1 binding sites,a series of dihydroindole derivatives were designed as novel LSD1 inhibitors in combination with LSD1 inhibitors reported in previous studies,and the representative compound with the strongest inhibitory ability,7e,was verified by in vitro and in vivo experiments.Therefore,in this study,the compound inhibitors 7d,7e,and 8k designed in the literature were selected to construct four protein-inhibitor complex systems: ligand-free binding of the empty protein LSD1,LSD1-7d,LSD1-7e,and LSD1-8k.Subsequently,molecular dynamics simulations of 500 ns were performed for each of the four systems,and the trajectories were analyzed at the end of the simulations: to explore dynamic conformational changes of LSD1 and its interactions after binding to inhibitors 7e,7d and 8k;probe the key residues in the binding process of inhibitors to LSD1;probe the changes at the active site of the protein when LSD1 binds to the more inhibitory 7e,which is different from other compounds.The conclusions are as follows:1,After molecular docking,the three ligand docking sites and their surrounding residues are essentially identical to key residues near the active pocket of LSD1 protein,such as residues Met332,Phe538,Tyr761,etc.2.After molecular dynamics simulations,it was found that compound 7e binds more tightly and stably to LSD1 compared to compounds 7d and 8k,leading to improved protein structural stability.Furthermore,when bound to 7e,LSD1 exhibited better inhibition of its binding to histones.3.The results of the interaction of LSD1 with compound inhibitors after molecular dynamics simulations showed that the ligand 7e formed more salt bridges,π-πinteractions,and hydrogen bonding interactions with key residues at the active pocket of LSD1 compared to compounds 7d and 8k.This resulted in stronger intermolecular interactions in the LSD1-7e complex and tighter binding,which was more favorable for inhibition.4.The results of binding free energy analysis show that the order of binding free energy from small to large is LSD1-7e < LSD1-8k < LSD1-7d.A smaller binding free energy indicates a stronger binding ability between the protein and ligand.Therefore,since 7e has the smallest binding free energy,it can be concluded that it binds most closely to LSD1 and has the strongest binding ability among the tested ligands.In summary,compound 7e exhibited the most stable structure,strongest intermolecular forces,and best inhibitory effect among the three inhibitor compounds tested.The molecular dynamics data and analysis presented in this study provide valuable insights and guidance for the design of novel LSD1 inhibitors.