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.　©　2023　Informa　UK　Limited,　trading　as　Taylor　&　Francis　Group.