A 3D pharmacophore model had been generated for a series of dipeptide proteasome 
inhibitors containing boron atoms using Catalyst. A data set consisting of 24 
inhibitors was selected on the basis of the information content of the 
structures and activity data as required by the Catalyst/HypoGen program. The 
built model was able to predict the activity of other known proteasome 
inhibitors not included in the model generation. Based on the analysis of the 
best hypotheses, some novel proteasome inhibitors were designed and predicted. 
Three dipeptide boronic acid inhibitors SMNT 1, SMNT 2, and SMNT 3, were 
synthesized and biologically assayed. It turned out that the three designed 
molecules were all more potent than the marketed MG341, and the experimental 
values were consistent with the predicted ones, indicating that the theoretical 
model was reliable enough to predict and design novel proteasome inhibitors. The 
covalent interaction mode between the boron atom of the inhibitor and 
O(gamma)-Thr1 residue of the 20S proteasome was studied for the first time by 
employing the most potent inhibitor SMNT 2 with the Insight II 2005/Affinity 
program. The docking results agreed well with the experimental ones.