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Docking and molecular dynamics studies on CYP2D6

Authors
  • Wang, JingFang1
  • Zhang, ChengCheng2
  • Wei, DongQing2
  • Li, YiXue1
  • 1 Chinese Academy of Sciences, Bioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institute for Biological Sciences, Shanghai, 200031, China , Shanghai (China)
  • 2 Shanghai Jiao Tong University, College of Life Science and Biotechnology, Shanghai, 200240, China , Shanghai (China)
Type
Published Article
Journal
Chinese Science Bulletin
Publisher
SP Science China Press
Publication Date
Jun 13, 2010
Volume
55
Issue
18
Pages
1877–1880
Identifiers
DOI: 10.1007/s11434-009-3697-z
Source
Springer Nature
Keywords
License
Yellow

Abstract

Drug-metabolizing enzymes, also known as cytochrome P450s, are a superfamily of hemoglobin responsible for metabolizing more than 90% clinical drugs. Cytochrome P450 2D6 (CYP2D6) is a significant member of cytochrome P450s for the reason of metabolizing about 20% clinical drugs. In this paper, molecular docking and molecular dynamic simulations are used to investigate the active site of CYP2D6, roles of essential amino acids within the active site and time-dependent protein energy changes. The results suggest that amino acids Glu216, Asp301, Ser304 and Ala305 in the active site are likely to form hydrogen bonding interactions with substrates; the benzene ring of Phe120 and aromatic ring in the substrates form Π-Π interactions. In addition, molecular dynamics simulations prove that the catalytic conformation of CYP2D6 without ligands can be obtained by their own atomic fluctuations. The impact of ligands on protein system energy and large conformational shift is not very large. Cytochrome P450s is known for their genetic polymorphisms, which will result in severe adverse drug reactions. Ideally, we hope to use molecular modeling to investigate the differences between the substrates of wild-type and mutants while they are bonded with drugs, and predict the drug metabolizing ability of mutants. Reduce the possibility for people taking drugs that they can not metabolize, therefore reduce the rate of adverse drug reactions, and eventually establish a platform of personalized drugs to largely benefit human health.

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