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The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Bottom Line: Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01.Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove.This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

ABSTRACT
Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

No MeSH data available.


Related in: MedlinePlus

Binding pockets and molecular docking results.(a) Primary binding pockets are illustrated with a representative HLA system. P1 (red), P3 (green), P4 (blue), P6 (purple), P7 (cyan), P9 (orange). (b) Molecular docking results. The top binding mode is illustrated for each HLA-ligand system.
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pone.0130928.g002: Binding pockets and molecular docking results.(a) Primary binding pockets are illustrated with a representative HLA system. P1 (red), P3 (green), P4 (blue), P6 (purple), P7 (cyan), P9 (orange). (b) Molecular docking results. The top binding mode is illustrated for each HLA-ligand system.

Mentions: HLA protein structures were prepared for docking according to a standard protocol involving removal of water and ions and protonation at physiological pH. Lapatinib was similarly prepared for docking, with rotatable bonds identified using the prepare ligand4.py script in AutoDockTools package [9]. For computational efficiency, the elongated HLA binding groove was divided into three overlapping volumes covering the full length of the groove (Fig 1); each volume was used in a separate docking run and the results were merged. For each binding volume, the side-chains of residues extending into the volume were modeled as flexible. The structure of lapatinib was obtained from DrugBank (http://www.drugbank.ca/) and the CHARMM and MMFF force fields were used to parameterize lapatinib. Docking was performed using AutoDock Vina [10] with DRB1*01:01, *07:01 and *15:01. The top scoring binding modes across all three search volumes (Fig 2) were selected for the MD simulations described below. Lapatinib was predicted to lie across the bottom of the binding groove interacting with pockets P1-P4 for DRB1*01:01 and P1-P6 for DRB1*07:01 and DRB1*15:01.


The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Binding pockets and molecular docking results.(a) Primary binding pockets are illustrated with a representative HLA system. P1 (red), P3 (green), P4 (blue), P6 (purple), P7 (cyan), P9 (orange). (b) Molecular docking results. The top binding mode is illustrated for each HLA-ligand system.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476721&req=5

pone.0130928.g002: Binding pockets and molecular docking results.(a) Primary binding pockets are illustrated with a representative HLA system. P1 (red), P3 (green), P4 (blue), P6 (purple), P7 (cyan), P9 (orange). (b) Molecular docking results. The top binding mode is illustrated for each HLA-ligand system.
Mentions: HLA protein structures were prepared for docking according to a standard protocol involving removal of water and ions and protonation at physiological pH. Lapatinib was similarly prepared for docking, with rotatable bonds identified using the prepare ligand4.py script in AutoDockTools package [9]. For computational efficiency, the elongated HLA binding groove was divided into three overlapping volumes covering the full length of the groove (Fig 1); each volume was used in a separate docking run and the results were merged. For each binding volume, the side-chains of residues extending into the volume were modeled as flexible. The structure of lapatinib was obtained from DrugBank (http://www.drugbank.ca/) and the CHARMM and MMFF force fields were used to parameterize lapatinib. Docking was performed using AutoDock Vina [10] with DRB1*01:01, *07:01 and *15:01. The top scoring binding modes across all three search volumes (Fig 2) were selected for the MD simulations described below. Lapatinib was predicted to lie across the bottom of the binding groove interacting with pockets P1-P4 for DRB1*01:01 and P1-P6 for DRB1*07:01 and DRB1*15:01.

Bottom Line: Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01.Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove.This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

ABSTRACT
Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

No MeSH data available.


Related in: MedlinePlus