On the human CYP2C9*13 variant activity reduction: a molecular dynamics simulation and docking study
Cytochrome P450 2C9 (CYP2C9) plays a key role in the metabolism of clinical drugs, CYP2C9 is a genetically polymorphic enzyme and some of its allelic variants have less activity compared to the wild-type form. Drugs with a narrow therapeutic index may cause serious toxicity to the individuals who cany such allele. CYP2C9*13, firstly identified by some of the present authors in a Chinese poor metabolizer of lomoxicam, is characterized by mutation encoding Leu90Pro substitution. Kinetic experiments show that CYP2C9*13 has less catalytic activity in elimination of diclofenac and lomoxicam in vitro. In order to explore the structure-activity relationship of CYP2C9*13, the three-dimensional structure models of the substrate-free CYP2C9*1 and its variant CYP2C9*13 are constructed on the basis of the X-ray crystal structure of human CYP2C9*1 (PDB code 1R9O) by molecular dynamics simulations. The structure change caused by Leu90Pro replacement is revealed and () the dramatic decrease of the enzymatic activity in clearance of the two CYP2C9 substrates: diclofenac and lomoxicam. The () of the bond between Pro90 and Asp89 in CYP2C9*13 is firstly identified. The backbone of residues 106-108 in CYP2C9*13 () over and their side chains block the entrance for substrates accessing so that the entrance of *13 shrinks greatly than that in the wild-type which is believed to be the dominant mechanism of the catalytic activity reduction. Consequent docking study which is consistent with the results of the kinetic experiments by Guo et al. identifies the most important residues for enzyme-substrate complexes.
Cytochrome P45O 2C9 CYP3C9*13 Genetic polymorphisms Structure-activity Molecular dynamics simulation
Y.-H.Zhou H.Zhou Q.-C.Zheng Z.-S.Li Y.Zhang M.Sun C.-C.Sun D.Si L.Cai Y.Guo
State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Life Science, Jilin University, Changchun 130023, China
国际会议
杭州
英文
1188-1196
2007-04-01（万方平台首次上网日期，不代表论文的发表时间）