Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1: molecular docking and 3D QSAR analyses

The Lamarckian genetic algorithm of AutoDock 3.0 has been employed to dock 40 1,5-diarylpyrazole class compounds into the active sites of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters and RMSD values compared with the known inhibitor, SC-558 (43), show that these inhibitors interact respectively with COX-2 and COX-1 in a very similar way. The r(2) values of 0.648 for COX-2 and 0.752 for COX-1 indicate that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of 1,5-diarylpyrazoles were reasonably explored, and the COX-2/COX-1 selectivity was demonstrated by the three-dimensional (3D) interaction models of inhibitors complexing with these two enzymes. Using the binding conformations of 1,5-diarylpyrazoles, consistent and highly predictive 3D quantitative structure-activity relationship (QSAR) models were developed by performing comparative molecular field analyses (CoMFA) and comparative molecular similarity analyses (CoMSIA). The q(2) values are 0.635 and 0.641 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by SC-558 (43) and a set of 10 other compounds that were not included in the training set. Mapping these models back to the topology of the active site of COX-2 leads to a better understanding of vital diarylpyrazole compounds and COX-2 interactions. Structure-based investigations and the final 3D QSAR results provided possible guidelines and accurate activity predictions for novel inhibitor design.