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.　©　2024　Editorial　Office　of　Huaxue　Tongbao.　All　rights　reserved.