# π–π Stacking mediated drug–drug interactions in human CYP2E1

@article{Liu2013SM,
title={$\pi$–$\pi$ Stacking mediated drug–drug interactions in human CYP2E1},
author={Yue Liu and B. Liu and Pei Hao and Xuan Li and Yi-Xue Li and Jing-Fang Wang},
journal={Proteins: Structure},
year={2013},
volume={81}
}
Because of having many low molecular mass substrates, CYP2E1 is of particular interests to the pharmaceutical industry. Many evidences showed that this enzyme can adopt multiple substrates to significantly reduce the oxidation rate of the substrates. The detailed mechanism for this observation is still unclear. In the current study, we employed GPU‐accelerated molecular dynamics simulations to study the multiple‐binding mode of human CYP2E1, with an aim of offering a mechanistic explanation for… Expand
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#### References

SHOWING 1-10 OF 59 REFERENCES
Structural basis for ligand promiscuity in cytochrome P450 3A4
• Chemistry, Medicine
• Proceedings of the National Academy of Sciences
• 2006
Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of ≈50% of marketed drugs. It is also the isoform most often involved in unwantedExpand
Structural dynamics of the cooperative binding of organic molecules in the human cytochrome P450 3A4.
• Chemistry, Medicine
• Journal of the American Chemical Society
• 2007
Molecular dynamics simulations for two enzymatic conformers and examined the differences between the substrate-free and the bound enzymes find that F304, in the interface between the active and effector binding sites, is a key residue in the mechanism of cooperative binding. Expand
Negatively cooperative binding properties of human cytochrome P450 2E1 with monocyclic substrates.
• Chemistry, Medicine
• Current drug metabolism
• 2012
Based on the structural analysis, a second substrate binding site is confirmed in human CYP2E1, and two important residues Thr303 and Phe478 are also identified to be the key factors in the cooperative binding on the short-range and long-range effects, respectively. Expand
Molecular modeling of two CYP2C19 SNPs and its implications for personalized drug design.
• Biology, Medicine
• Protein and peptide letters
• 2008
The structure-activity relationships of two SNPs, W120R and I331V, with the ligands of CEC, Fluvoxamine, Lescol and Ticlopidine were investigated, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs. Expand
3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design.
• Chemistry, Medicine
• Biochemical and biophysical research communications
• 2007
The binding pockets of CYP2C19 for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs. Expand
Molecular dynamics simulations of CYP2E1.
• Chemistry, Medicine
• Medicinal chemistry (Shariqah (United Arab Emirates))
• 2012
The active site interact with the aromatic substrates mainly through π-π stacking, supplied by five hydrophobic phenylalanines in the active site, stimulating novel strategies for conducting further mutagenesis studies for specific drug design. Expand
Multiple Sequential Steps Involved in the Binding of Inhibitors to Cytochrome P450 3A4*
• Chemistry, Medicine
• Journal of Biological Chemistry
• 2007
A three-step minimal model for inhibitor binding is proposed, developed with kinetic simulations, consistent with the previously reported model for the binding of substrates, although it is possible that even more steps are involved. Expand
Allosteric P450 mechanisms: multiple binding sites, multiple conformers or both?
• Medicine
• Expert opinion on drug metabolism & toxicology
• 2008
Application of the concept of an oligomeric allosteric enzyme to microsomal cytochromes P450 in combination with a general paradigm of multiple ligand occupancy of the active site provides an excellent explanation for complex manifestations of the atypical kinetic behavior of the enzyme. Expand
Multiple-ligand binding in CYP2A6: probing mechanisms of cytochrome P450 cooperativity by assessing substrate dynamics.
• Chemistry, Medicine
• Biochemistry
• 2008
Evidence is presented that CYP2A6 accommodates multiple ligands and that intramolecular isotope effect experiments can provide insight into the mechanisms of multiple-ligand binding and the utility of kinetic isotope effects in characterizing allosteric CYP behavior. Expand
Kinetics and Thermodynamics of Ligand Binding by Cytochrome P450 3A4*
• Chemistry, Medicine
• Journal of Biological Chemistry
• 2006
A three-step substrate binding model is proposed, based on absorbance and fluorescence stopped-flow kinetic data and equilibrium binding data obtained with bromocriptine, and evaluated using kinetic modeling. Expand