Discovery Of New LSD1 Inhibitor YJ22 And Its Binding Model Analysis

In recent years,scientists have found that the occurrence and development of tumor always accompanied by changes in epigenetic cell.More and more experiments have proved that the change of epigenetics can cause the occurrence of tumor,and the role of epigenetics in tumor treatment has been paid more and more attention.In epigenetics,both methylation and demethylation of histones play an important role.Histone lysine specific demethylase 1（LSD1）is a kind of amino oxidase dependent on flavin adenine dinucleotide（FAD）,which can demethylate histone.The results showed that when the drug was used to inhibit LSD1 activity,the growth of tumor was inhibited and the side effects were low.Thus,LSD1 inhibitors become a light on the way to cancer.At present,most of LSD1 inhibitors have been found based on the MAO inhibitor tranylcryptoline（TCP）,while TCP as the skeleton inhibitors are irreversible inhibitors.However,there are some disadvantages of such irreversible inhibitors,such as reducing platelet and neutrophil,causing myelofibrosis and lymphoid organ diseases.At present,LSD1 inhibitors have not entered the clinical treatment stage.Therefore,it is very important to find a new LSD1 inhibitor.In this paper,the new LSD1 inhibitors were found by the method of computer-aided drug design.The specific research contents are as follows:First,Glide with good docking accuracy and quality was selected as docking software.The crystal structure of LSD1（PDB ID:5x60）,which combines the ligand FAD and histone H3 substrate simultaneously,was selected as the docking acceptor,and the FAD pocket and H3 substrate pocket of LSD1 were selected as the docking sites.Small molecules from Chemdiv,Lifechemicals,Maybridge,which have a variety of skeletons and a large number of skeletons,were selected as docking ligands for molecular docking of more than 3 million compounds.The docking results were integrated to exclude the compounds that did not conform to the ribinsky five rule,and the remaining compounds were treated with FCFP＿4 molecular fingerprints.The similarity was expressed by Tanimoto similarity coefficient,and molecular clustering was performed by Pipeline pilot software.Finally,30 compounds were selected and purchased for activity test.The inhibition rate of YJ22 was 98.2%at the concentration of 10μM.the IC₅₀ of YJ22 was 2.364μM.Second,the best active compound YJ22 was analyzed.First of all,the flexible docking experiment of compound YJ22 in the FAD pocket and H3 substrate pocket of LSD1 was carried out by using Schr（?）dinger’s Induced Fit Docking module.Finally,the binding mode of YJ22 in the FAD pocket and H3 substrate pocket was obtained.Then,by comparing the binding mode of YJ22 with the existing LSD1 inhibitors and the ligand FAD of LSD1,we found that the binding mode of YJ22 with other LSD1inhibitors in the FAD pocket is similar to that of FAD.At the same time,the binding conformation of YJ22 in FAD pocket is similar to that of FAD,the natural ligand of LSD1.There are two possible binding modes of YJ22 in H3 pocket,but the binding mode of YJ22 in H3 pocket is not similar to that of other inhibitors in H3 pocket.Third,in order to determine the stability of YJ22 binding mode and the key of YJ22 binding LSD1,we carried out molecular dynamics simulation of YJ22 binding mode.The results show that YJ22 has the best combination mode stability in FAD pocket.At the same time,we found that the 2,4-quinazolin Dione ring of YJ22 is the key to its binding with LSD1.According to the key functional groups of YJ22 and its conformation when binding with LSD1,we further designed the pharmacophore model,and verified it by the compounds with measured activity.Through the above research work,we found a novel LSD1 inhibitor YJ22 which has never been reported before,and gave the binding mode of YJ22 by molecular docking and other means.At the same time,we designed a reliable pharmacophore model according to the binding mode of YJ22.This work provides important information for the research of LSD1 inhibitors,and has certain reference significance for the discovery of novel LSD1 inhibitors based on structure.