Novel selective inhibitors of hydroxyxanthone derivatives for human cyclooxygenase-2

Aim:To screen the selective inhibitors for human cyclooxygenase-2 ((h)COX-2)utilizing molecular simulation.Methods:Eight xanthone derivatives,compoundsA-H,were employed by the structure-based research methodology.Resveratroland 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 thecomplexes were calculated by CHARMm forcefield.Results:NS-398 could notdock into the active site of COX-1.However,resveratrol,the specific selectivecompound for COX-1,gained lower interaction energy while docked in COX-1.The lower interaction energies were investigated,while compound B and F weredocked 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-1and COX-2.Conclusion:The conformations of the docking would influence thevalues of interaction energies.The hydrogen bond could also increase the stabi-lity of the whole complex,which might suggest that compound B had a suitableconformation in the tunnel-like active site of COX-1.Compound F,a potent agentfor COX-2,revealed a strong hydrogen bond with Ser516 in human COX-2 to forma stable complex.