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Topomer comparative molecular field analysis (Topomer CoMFA) and holographic quantitative structure-activity relationship (HQSAR) for 130 2,5-diketopiperazine dervatives were used to build a three-dimensional quantitative structure-activity relationship (3D-QSAR) model.The results show that the models have high predictive ability.For Topomer CoMFA,the cross-validated q2 value is 0.710 and the non-cross-validated r2 value is 0.834.The most effective HQSAR model shows that the cross-validation q2 value is 0.700,the non-cross-validated r2 value is 0.815,and the best hologram length value is 353 using connections and bonds as fragment distinctions.50 highly active 2,5-diketopiperazine derivatives were designed based on the three-dimensional equipotential map and HQSAR color code map.Finally,the molecular docking method was also used to study the interactions of these new molecules by docking the ligands into the diketopiperazine active site,which revealed the likely bioactive conformations.This study showed that there are extensive interactions between the new molecule and Arg156,Arg122 residues in the active site of diketopiperazine.These results provide useful insights for the design of potent of the new 2,5-diketopiperazine derivatives.