Abstractí¬It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes
involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig
out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics
(MD) simulations, automated docking, and 3D-QSAR analyses were performed in this study on 21 COX-2/5-LOX dual inhibitors,
namely, 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (DHDMBF) analogues. A 3D-model of 5-LOX was built based on the
high-resolution X-ray structure of rabbit reticulocyte 15-lipoxygenase. Molecular docking was then applied to locate the binding
orientations and conformations of DHDMBF analogues with COX-2 and 5-LOX, respectively, leading to highly predictive CoMFA
models constructed on the basis of the binding conformations with q2 values of 0.782 and 0.634 for COX-2 and 5-LOX, respectively.
In addition, CoMFA field distributions were found in good agreement with the structural characteristics of the corresponding binding
sites. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature
with a moderately bulky group at R2 position and a rather negatively charged group around the position of the carbonyl group of
DHDMBFs. Therefore, the final 3D-QSAR models and the information of the inhibitorĘCenzyme interaction should be useful in
developing new NSAIDs as anti-inflammation drugs with favorable safety profile.