In silico approaches for the identification of novel ULK1 inhibitors: pharmacophore model, molecular docking and molecular dynamics simulations

The serine/threonine kinase unc-51-like autophagy activating kinase 1 (ULK1) has been regarded as an attractive target for tumor therapy. In this study, in silico approaches, such as the pharmacophore-based virtual screening strategy, molecular docking and molecular dynamics (MD) simulations, were applied to develop novel potential ULK1 inhibitors. The pharmacophore models based on known aminopyrimidine ULK1 inhibitors were constructed to screen the dataset of 1.68 million compounds, which were obtained via screening the 2.30 million compounds in ChEMBL database by Lipinski's rule of five. Seven novel compounds and 1 known ULK1 inhibitor stand out for the strong virtual biological activity by molecular docking, cluster analysis, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation and Absorption Distribution Metabolism Excretion Toxicity (ADMET) prediction. Their results of MD included principal component analysis (PCA) and Free Energy Landscapes surface (FELs) indicated that the protein-ligand complex was stable in simulated trajectories of 100 ns. The binding free energy (BFE) calculations showed that a total of 6 novel compounds (CL130, CL834, CL961, CL966, CL163 and CL329) with the stable binding state and stronger BFE (-61.17 to -37.01 kcal/mol) than that of original ligand 3RF (-36.66 kcal/mol). With reference to the ULK1 inhibition of 3RF (IC₅₀ = 160 nM), it can be inferred that these compounds could be used as a new type of potential ULK1 inhibitors and be worthy of further investigation for tumor treatments.Communicated by Ramaswamy H. Sarma.