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The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is tightly related to Digestive System Neoplasms genesis. Therefore, inhibitors that target RIPK1 have gained popularity in today's anti-cancer therapy. Molecular docking, molecular dynamics simulations, and molecular mechanics/Poisson-Boltzmann surface area calculations were used to investigate the binding mode and inhibition mechanism of five 4,5-dihydropyrazole derivatives with RIPK1 in the present work. The results showed that the five inhibitors mainly interacted with RIPK1 through van der Waals interaction and were stably present in the hydrophobic pocket next to the ATP-binding pocket. During the simulation, the inhibitor 2R with opposite chirality displayed a significant flip-flop in the binding pose, causing the key residue Asp156 to not easily maintain the inactive conformation, affecting its inhibitory ability. Inhibitors with identical chirality but different 1-substituents could exert noncompetitive inhibition via three pathways. First of all, the inhibitor interacted directly with ATP, influencing its γ -phosphate position. Second, it altered the conformation of Lys45, which was crucial for both ATP binding and γ -phosphate transfer. And then it affected the conformation of the P-loop and ß1 sheet, resulting in differences in substrate peptide recognition. The results can provide a theoretical basis for the design of such inhibitors in the future. [ABSTRACT FROM AUTHOR]