Design of Nonclassical DHFR Inhibitors by CoMFA and CoMSIA 3D QSAR Studies

Dihydrofolate reductase is known for important role in cancer and microbial diseases and hence is considered as validated target for aforementioned diseases. Three dimensional quantitative structure activity relationship studies (3D-QSAR) involving comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were performed using twenty two Pneumocystis carinii pyridopyrimidine dihydrofolate reductase inhibitors to find out the structural relationship with the activity. An atom fit alignment yielded best predictive CoMFA model with cross-validated r2 value of 0.678, noncross-validated r2 value of 0.977 and standard error of estimate 0.077. In Similar fashion, an excellent CoMSIA model was developed with q2 of 0.415, noncrossvalidated r2 of 0.965 and standard error of estimate of 0.11. Both models predicted the activity of internal test set molecules efficiently within an acceptable error range. Further, models were employed to predict the activity of seven new compounds. The predicted activities of some of these designed compounds were found nearly equal to that of potent compound of study series.