Novel selective inhibitors of hydroxyxanthone derivatives for human cyclooxygenase-2.
OBJECTIVE
To screen the selective inhibitors for human cyclooxygenase-2 ((h)COX-2) utilizing molecular simulation.


METHODS
Eight xanthone derivatives, compounds A-H, were employed by the structure-based research methodology. Resveratrol and NS-398 were selected as the control compounds for COX-1 and COX-2, respectively. The docking results were scored and the interaction energies of the complexes were calculated by CHARMm forcefield.


RESULTS
NS-398 could not dock into the active site of COX-1. However, resveratrol, the specific selective compound for COX-1, gained lower interaction energy while docked in COX-1. The lower interaction energies were investigated, while compound B and F were docked into the catalytic sites of COX-1 and COX-2, respectively. Compound A, 1,3,6,7-tetrahydroxyxanthone, revealed high inhibitory potency to both COX-1 and COX-2.


CONCLUSIONS
The conformations of the docking would influence the values of interaction energies. The hydrogen bond could also increase the stability of the whole complex, which might suggest that compound B had a suitable conformation in the tunnel-like active site of COX-1. Compound F, a potent agent for COX-2, revealed a strong hydrogen bond with Ser516 in human COX-2 to form a stable complex.
Chen
Yu-chian
YC
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan China. ycc@mail.cmu.edu.tw
Chen
Kun-tze
KT
D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D044004:Xanthones / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D044004:Xanthones; D051546:Cyclooxygenase 2