CoMFA/CoMSIA/HQSAR and Docking Study of the Binding Mode of Selective Cyclooxygenase (COX‐2) Inhibitors

Chen, Haifeng; Li, Qiang; Yao, Xiaojun; Fan, BoTao; Yuan, Shengang; Panaye, A.; Doucet, J. P.

The intermolecular interaction between four types of anti‐inflammatory inhibitors (oxazoles, pyrazoles, pyrroles and imidazoles) and COX‐2 receptor was studied. The results of docking suggest that they have similar interaction mechanism. The most active compounds of these four types of inhibitors could both form several hydrogen bonds with residues His90, Arg513, Leu352 and Arg120, and develop hydrophobic interaction with residues Phe518, Leu352 and Leu359. This is consistent with the investigation reported by R. G. Kurumbail et al. (Nature. 1996, 384, 644‐648). A common 3D‐QSAR model could be constructed with these four categories of COX‐2 inhibitors using the method of docking‐ guided conformer selection. The cross‐validated q(2) values are found as 0.741 and 0.632 for CoMFA and CoMSIA respectively. And the non‐cross‐validated r(2) values are 0.887 and 0.885. 54 inhibitors constitute the test set used to validate the model. The results show that this model possesses good predictive ability for diverse COX‐2 inhibitors. Furthermore, a HQSAR model was used to evaluate the influence of substituents on anti‐inflammatory activity. Compared with the results of previous works, our model possesses significantly better prediction ability. It could help us to well understand the interaction mechanism between inhibitors and COX‐2 receptor, and to make quantitative prediction of their inhibitory activities.