2D-QSAR Of LSD 1 Inhibitors,Molecular Docking And Molecular Dynamics Simulation Studies

Purpose:More and more evidence suggests that epigenetic variations,especially those involving histones,are involved in the onset and progression of various cancers.Histone lysine specific demethylase 1(LSD1)is a flavin adenine dinucleotide(FAD)dependent amine oxidase that can specifically recognize H3K4 and H3K9 substrates and remove their monomethyl or dimethyl modifications.It mediates many intracellular signaling pathways and is closely related to the occurrence and development of tumors.Therefore,using quantitative structure-activity relationship(QSAR),molecular docking,and molecular dynamics simulation methods to develop efficient and specific LSD1 inhibitors is not only beneficial for studying the biological functions of LSD1,but also has important scientific significance for the development of anti-tumor drugs.Methods:1.Calculating in CODESSA software and select accurate descriptors from the descriptor pool based on heuristic method(HM),and establish a multiple linear regression model to predict the activity of new LSD1 inhibitor drugs.2.An optimal nonlinear quantitative structure-activity relationship(QSAR)model with descriptors was established using gene expression programming(GEP).3.The corresponding pharmacophore model was constructed according to the residue type and exclusion volume of LSD1 protein active site.4.Obtain the molecular set of active monomers of traditional Chinese medicine from TCMSP traditional Chinese medicine database.The compounds in the database are matched with the characteristics of pharmacophore in order to carry out virtual screening,molecular docking analysis and ADME prediction.According to the scoring evaluation of the unified standard,select compounds with high matching degree with the characteristics of the pharmacophore for research.5.Conduct molecular dynamics simulation on the compound and LSD1 protein complex to evaluate and verify the stability of the complex binding mode.Results:1.Heuristic method(HM)screens out four descriptors,and we obtain a ranking of the impact of descriptors on the activity of LDS1 inhibitors: Complementary Information content>HACA-2/TMSA>Min partial charge for a H atoms>Relative number of rings.2.Gene expression programming(GEP)results obtained the optimal nonlinear QSAR model for the training and testing sets,with correlation coefficients of 0.92 and0.80,and average errors of 0.07 and 0.60,respectively.3.The AADDR pharmacophore model was constructed,and it was obtained that LSD1 inhibitors need to have the structural characteristics of hydrogen bonds and aromatic rings.4.Based on the ADME prediction and docking scoring results,molecular docking experiments were carried out to screen a new LSD1 inhibitor hiloside,and the ADME prediction result of this compound was 0,indicating that this compound has excellent absorption,distribution,metabolism and excretion capabilities.5.The results of molecular dynamics simulation showed that the binding mode of LSD1 and stilbene was stable.Conclusion:In this study,a 2D-QSAR model and a pharmacophore model were constructed,and a new LSD1 inhibitor was obtained through molecular docking experiments,molecular dynamics simulation and ADME prediction results,and the stability and absorption,distribution,metabolism and excretion capacity of the drug were verified.These findings provide new value for the design of LSD1 inhibitors as highly selective first-class clinical candidates.Once the model and drug are developed and validated,it will guide the design of more effective anti-tumor drugs.