Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine...

3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, K(i), and the inhibitor concentrations, IC90 of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent groups such as: benzyl, isopropyl, 4-hydroxybenzyl, ketone, oxime, pyrazole, imidazole, triazole and having anti-HIV-1 protease activities. A significant cross-validated correlation coefficient (q2) of 0.63 and a fitted correlation coefficient r2 of 0.70 were obtained, indicating that the models can predict the anti-protease activity from poorly to highly active compounds reliably. The best predictions were obtained for: XV643 (predicted log 1/K(i) = 9.86), a 3,5-dimethoxy-benzyl cyclic urea derivate (molec60, predicted log 1/K(i) = 8.57) and a benzyl cyclic urea derivate (molec 61, predicted log 1/IC90 = 6.87). Using the CoMFA method, we also predicted the biological activity of 14 cyclic urea derivatives that inhibit the HIV-1 protease mutants V82A, V82I and V82F. The predicted biological activities of the: (i) XNO63 (inhibitory activity on the mutant HIV-1 PR V82A), (ii) SB570 (inhibiting the mutant HIV-1 PR V82I) and also (iii) XV652 (during the interaction with the mutant HIV-1 PR V82F) were in good agreement with the experimental values.