Discovery of Novel ULK1 Inhibitors Based on Virtual Screening and Molecular Dynamics Simulation
Unc-51-like autophagy-activating kinase 1(ULK1)is a crucial regulator of autophagy initiation and serves as a significant target for tumor therapy.Firstly,the pharmacophore model based on known ULK1 inhibitors was constructed.The methods,such as pharmacophore model screening,molecular docking and Molecular Mechanics/Generalized Born Surface Area(MM/GBSA)binding free energy calculation,were used to screen approximately 520,000 drug-like small molecules in the database to identify compounds with high theoretical affinity.Subsequently,50ns molecular dynamics(MD)simulation was performed to validate the binding stability of the protein-ligand complexes and the average binding free energy(BFE)of the last 10 ns was calculated to verify the binding ability of the ligands accurately.The results showed that the 6 compounds(F5258-0159,F3407-0428,F0529-1100,F0696-3531,F3222-5280,F6525-5596)have novel skeletons,excellent molecular docking fraction and binding free energy and stable binding state with ULK1.They can be used as new potential ULK1 inhibitors for the research of tumor therapy,which also provided new research ideas for the design and development of new ULK1 inhibitors.
NETL
NSTL
万方数据
维普
