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1 Introduction

View Preview. Learn more Check out. Abstract Understanding the way in which drugs are metabolized by cytochrome P 2D6 CYP2D6 and hence the underlying mechanisms that define potential toxicity is crucial to avoid adverse reactions. Citing Literature. Related Information. Close Figure Viewer. Browse All Figures Return to Figure. Previous Figure Next Figure.

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Email or Customer ID. Altmetric -. Citations Abstract Human cytochrome P P 1A2 is involved in the oxidation of many important drugs and carcinogens. Supporting Information Available. Cited By. This article is cited by 32 publications. Zuzana Jandova, Samuel C. Gill, Nathan M.

Lim, David L. Mobley, Chris Oostenbrink. Binding Modes and Metabolism of Caffeine. Chemical Research in Toxicology , 32 7 , DOI: Nagy, Chul-Ho Yun, and F. Peter Guengerich. Biochemistry , 53 39 , Chemical Reviews , 2 , The Journal of Physical Chemistry B , 16 , Journal of the American Chemical Society , 34 , The Journal of Physical Chemistry B , 20 , Peter Guengerich,, Joel A. Krauser, and, William W. Biochemistry , 43 33 , Chemical Research in Toxicology , 14 6 , Yasushi Yamazoe, Kouichi Yoshinari.

Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions.

Effect of Evodiamine on CYP Enzymes in Rats by a Cocktail Method

Drug Metabolism and Pharmacokinetics , 32 5 , Part 1. Focusing on polycyclic arenes and the related chemicals. Drug Metabolism and Pharmacokinetics , 31 5 , Joy M.

Hung, Homayon J. Synthesis and cytotoxicity of thieno[2,3-b]pyridine and furo[2,3-b]pyridine derivatives. European Journal of Medicinal Chemistry , 86 , Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome Pcatalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry. The approach also includes information from experimental inhibition studies and chemical information from ligands. However, in the absence or in the presence of bound ligands, important conformational changes are observed.

This structure was repaired using an in silico protocol Supplementary Fig. In our study, the structure called apo is the rebuilt one.


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By comparing the two X-ray structures, apo and holo Supplementary Fig. S2 , a striking difference appears: the apo structure Supplementary Fig. S2D , it is seen that proteins share a similar fold, but considerable differences appear around the helix F.

Diversity in Mechanisms of Substrate Oxidation by Cytochrome P450 2D6

Residues E and D Supplementary Fig. S3A and Supplementary Data. By comparing the orientation of key residues between the apo and holo X-ray structures, we observe that D orientation Supplementary Fig. S3A is conserved maintaining its interaction with F In order to explore further the conformational space of the CYP2D6 active site, we performed MD simulations with three representative and diverse CYP2D6 substrates propafenone, mexiletine and codeine; Fig.


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  • We performed docking experiments with propafenone, mexiletine and codeine. The positions of the SOMs in the docking poses guided the selection of the best poses. Docking of propafenone Fig. Docking of mexiletine Fig. The codeine Fig. Being a large and rigid compound, docking of codeine in the rigid binding site was not completely successful, highlighting the importance of considering protein flexibility for such cases. A Propafenone shown in sticks in magenta atom type. B Mexiletine shown in sticks in cyan atom type.

    C Codeine shown in sticks in mauve atom type. After docking, we ran MD simulations. Four MD simulations have been performed on the apo structure, three in complex with the three ligands Fig. Starting from the holo X-ray structure, we ran two MD simulations, one with the co-crystallized ligand pinomastat and another without a bound ligand, and thus, in total, six MD simulations were carried out.

    During the entire MD simulations the bound propafenone, mexiletine or codeine remained stable in the active site showing small fluctuations of the distances to the Fe heme. Different strategies can be employed in order to select MD-derived representative structures for further analysis.

    Considering so many structures for docking without any classification is not efficient because many redundant structures of the binding site can be present. In this study, we successfully reduced the number of structures by applying HAC based on RMSD of all atoms of the binding sites to the extracted structures. Initially, structures were extracted for each MD simulation, and thus structures in total were generated.

    After our procedure, we obtained 6 structures from the trajectory based on the apo 2F9Q, 8 structures from the trajectory based on the 2F9Q complexed with propafenone, 5 structures from the trajectory based on the 2F9Q complexed with mexiletine, 5 structures from the trajectory based on the 2F9Q complexed with codeine, 7 structures from the trajectory based on the apo 3QM4 and 3 structures from the trajectory based on the 3QM4 in complex with its co-crystallized ligand prinomastat in total 34 MD-derived structures.

    Our curated dataset contained active and inactive compounds Supplementary Fig.

    Cytochrome P450

    We performed virtual screening experiments of this dataset on 34 MD-derived structures and we compared the enrichment results with those of the two experimental structures Supplementary Fig. S5A retrieved active compounds similarly to the experimental structures. S5C discriminate better the active compounds than the two experimental structures. S5B , MD3 performed twice better than the X-ray structures.

    Similarly, MD5 and MD6 retrieved more active compounds than the X-ray structures in the early stage of enrichment. From a structural point of view, MD1 Fig. MD2 Fig. Regarding MD5 Fig. MD6 Fig. Our protocol allowed to extract diverse conformations of the binding sites, four of them showing a better or similar discrimination of the active compounds than the X-ray structures.

    MD-derived structures with the heme moiety shown in orange sticks. B MD2 structure colored in blue extracted from the apo 3QM4 trajectory. C Superimposition of MD3 and MD4 structures colored in green and pink, respectively extracted from the 2F9Q complexed with propafenone trajectory.

    Cytochrome P 2D6 | Structure, Function, Regulation and Polymorphism | Taylor & Francis Group

    D MD5 structure colored in yellow extracted from the 2F9Q complexed with mexiletine trajectory. E MD6 structure colored in orange extracted from the 2F9Q complexed with mexiletine trajectory. We analyzed the differences in the binding site that could be involved in discriminating inhibitors and non-inhibitors. MD1 structure shows enrichment close to the X-ray holo structure Supplementary Fig.