A Novel Cytoskeleton Inhibitor Of Aldosterone Reductase 1C3(AKR1C3) For The Treatment Of Leukemia

Aldosterone reductase 1C3(AKR1C3)overexpression in human body can lead to leukemia.Therefore,aldosterone reductase 1C3 is a potential target for the treatment of acute myeloid leukemia and T-cell acute lymphoblastic leukemia.AKR1C31 inhibitors can assist in the treatment of leukemia drugs,play a better role,increase the drug resistance of patients,and make patients get better treatment plan.Although there are anti leukemia drugs on the market,the problem of drug resistance still can not be solved.Therefore,it is still of great significance to find novel skeleton AKR1C3 inhibitors by virtual screening.For 51 Bacillin derivatives,eight of them were selected to construct pharmacophore model to verify the reliability of pharmacophore model.Then virtual screening based on validated pharmacophore model,molecular docking,target prediction and biological activity test based on HL60 cells were carried out to find potential new AKR1C3 inhibitor skeleton.Firstly,eight Bacillin derivatives(Z1-Z8)were selected as training set to construct 20 pharmacophore models,and the optimal pharmacophore model model was obtained through bait test＿016(the enrichment degree was 21.5117 and the fitting optimization degree was 0.9668).Then the optimal pharmacophore model model is used MODEL＿016 to conduct a virtual screening of zinc database.Then the screened 83256 small molecular compounds were molecular docking with AKR1C3 protein eutectic,and scored according to the docking with the original ligand Compared with the interaction force,16532 candidate compounds with higher docking score and interaction with important residues PHE306 and TRP227 of receptor protein were screened out.After that,eight novel candidate compounds with novel skeleton were screened.Finally,we chose to purchase two candidate compounds A3 and A7.Because compared with the other six compounds,these two compounds have higher molecular docking score,better target prediction and better ADMET prediction results.Finally,the biological activity of the two compounds A3 and A7 were tested in vitro based on cell level.The results of the in vitro bioactivity tests of compounds A3 and A7 were 268.3um and 88.94 um,respectively.The above research methods can also provide an important reference for the development of new anti leukemia drugs with AKR1C3 inhibitors.