Application of 3D-QSAR on a Series of Potent P38-MAP Kinase Inhibitors

One of the most applied methods in drug industry for development of new drugs is 3D QSAR methodology. As p38-mitogen-activated protein kinase (p38-MAPK) plays a crucial role in regulating the production of such proinflammatory cytokines as tumor necrosis factor-α (TNF-α) and interleukin-1, emerging as an attractive target for new anti-inflammatory agents, we used a 3D-QSAR based method of Comparative Molecular Field Analysis (CoMFA) on a series of 52 potent p38-MAP kinase inhibitors with IC50 ranging from 3.2 to 10,000 nM. An alignment rule for the compounds was defined using Distill in SYBYL 7.3. The best model was validated using a data set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields and biological activities (pIC50). The best predictions were obtained with a CoMFA region-focusing model (R2 ncv = 0.952, q2 = 0.678, R2 Pred = 0.627). The statistical parameters from the model indicate that the data are well fitted and has high predictive ability. Moreover, the resulting 3D CoMFA contour maps provide useful guidance for designing highly active inhibitors.