3D-QSAR studies of boron-containing dipeptides as proteasome inhibitors with CoMFA and CoMSIA methods.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of dipeptide boronate proteasome inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 46 molecules served to establish the models. The optimum CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.676 and 0.630 and conventional coefficients (r(2)) of 0.989 and 0.956, respectively. The predictive capacities of both models were successfully validated by calculating a test set of 13 molecules that were not included in the training set. The predicted correlation coefficients (r(2)(pred)) of CoMFA and CoMSIA are 0.963 and 0.919, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models constructed in this paper can be used to guide the development of novel dipeptide boronate inhibitors of 20S proteasome.
Zhu
Yong-Qiang
YQ
Jiangsu Simcere Pharmaceutical Research Institute, No. 699-18 Xuan Wu Avenue, Xuan Wu District, Nanjing 210042, PR China. zhuyongqiang@simcere.com
Lei
Meng
M
Lu
Ai-Jun
AJ
Zhao
Xin
X
Yin
Xiao-Jin
XJ
Gao
Qing-Zhi
QZ
D001895:Boron / Q000737:chemistry*; D003198:Computer Simulation; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D061988:Proteasome Inhibitors; D021281:Quantitative Structure-Activity Relationship
D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; D061988:Proteasome Inhibitors; D001895:Boron