Acta Pharmacologica Sinica 2007 December; 28 (12): 2027-2032; doi: 10.1111/j.1745-7254.2007.00663.x

Aim: 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.

Conclusion: The conformations of the docking would influence the values of interaction energies. The hydrogen bond could also increase the stabi-lity 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.

Keywords: cyclooxygenase; non-steroidal anti-inflam-matory drugs; xanthone; molecular simulation; interaction energy; inhibitors