The metabolism of CYP2C9 and CYP2C19 for gliclazide by homology modeling and docking study.
With homology modeling techniques, a 3D structure model of CYP2C19 was built and refined with molecular mechanics and molecular dynamics simulations. The refined model was assessed to be reasonable by Profile-3D and PROCHECK programs. With the aid of the automatic molecular docking, one substrate and two inhibitors were docked to CYP2C19 by InsightII/Affinity program. The docking results, which are in well agreement with the reported results, demonstrate that the refined model of CYP2C19 is reliable. Then, with the refined model of CYP2C19 and the crystal structure of CYP2C9, the metabolisms of them for gliclazide in two different metabolic pathways were studied and the results show that both enzymes have more favorable interaction energies and stronger affinity with gliclazide in methylhydroxylation pathway than in 6beta-hydroxylation pathway. It is exciting that substrate inhibition phenomenon can be found in metabolisms of CYP2C9 and CYP2C19 for gliclazide in two metabolic pathways. Gliclazide can change the conformation of the active sites and decrease obviously the affinities between gliclazide in the active site and enzymes when it is docked in the second active sites in CYP2C9 and CYP2C19. These results are in well agreement with the kinetic experimental results.
Yao
Yuan
Y
Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun 130023, PR China.
Han
Wei-Wei
WW
Zhou
Yi-Han
YH
Li
Ze-Sheng
ZS
Li
Qiang
Q
Chen
Xiao-Yan
XY
Zhong
Da-Fang
DF
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D020134:Catalytic Domain / Q000187:drug effects; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005907:Gliclazide / Q000737:chemistry*; D006801:Humans; D006900:Hydroxylation; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects
C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D005907:Gliclazide