Identification of Novel Substrate-competitive Inhibitors for PRMT5 by Virtual Screening and Biological Evaluation
Protein arginine methyltransferase 5(PRMT5)is one of the important members of type Ⅱ PRMTs,and its overexpression is closely related to cancer development and progression,which is an important target for tumor therapy.In order to obtain novel substrate-competitive inhibitors for PRMT5,the Specs and ChemDiv com-pound libraries were screened through virtual docking,pharmacophore modeling and screening,Lipinski and AD-MET screening based on the crystal complex structure of the receptor PRMT5 with the ligand EPZ015666(PDB ID:4X61).The PRMT5 enzyme activity test was performed for the selected 12 compounds.The results showed that compounds E749-0026 and Y512-7443 exhibited significantly better inhibitory activities against PRMT5 than the other tested compounds at a concentration of 1 μM;molecular docking showed that these two compounds bind to PRMT5 through hydrogen bonding,electrostatic forces and hydrophobic interactions.Compounds E749-0026 and Y512-7443 can be used as lead compounds for further studies as substrate-competitive inhibitors for PRMT5.
万方数据
维普
