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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

Simulated structures of trimer-HLA system.HLA-DRB1*01:01-Frame 2 (a-c), HLA-DRB1*01:01-Frame 3 (d-f), HLA-DRB1*07:01 (g-i) and HLA-DRB1*15:01 (j-l). (a), (d), (g) and (j): Alignment of initial structure (red) and a representative structure (blue). (b), (e), (h) and (k): Sausage plot of the structure where the color and the thickness of HLA are proportional to the RMSF of α carbon. The color scales for the sausage plots are the same throughout this document. (c), (f), (i) and (l): The volume occupied by lapatinib and peptide. The blue envelope outlines the 50% occupancy volume of the drug (red) and peptide (green).
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pone.0130928.g007: Simulated structures of trimer-HLA system.HLA-DRB1*01:01-Frame 2 (a-c), HLA-DRB1*01:01-Frame 3 (d-f), HLA-DRB1*07:01 (g-i) and HLA-DRB1*15:01 (j-l). (a), (d), (g) and (j): Alignment of initial structure (red) and a representative structure (blue). (b), (e), (h) and (k): Sausage plot of the structure where the color and the thickness of HLA are proportional to the RMSF of α carbon. The color scales for the sausage plots are the same throughout this document. (c), (f), (i) and (l): The volume occupied by lapatinib and peptide. The blue envelope outlines the 50% occupancy volume of the drug (red) and peptide (green).

Mentions: Each of the trimer simulations is energetically stable (Fig 6a). This is not unexpected because the trimer models were built from the output of the lapatinib-bound HLA and peptide-bound HLA simulations, which all contained stable HLA conformations by the end of the simulations. Although both lapatinib and peptide contribute a relatively small percent of the total system energy and thus their effect is not seen in the graph, the forces applied to each molecule through the MD simulation are still maintained and the compounds move accordingly. Therefore, while we see conformation changes in Fig 7, the energy plot can appear relatively flat. Fig 6b shows that the flexibility of the HLA molecule is very similar in all simulations. Overall, the presence of peptide and lapatinib slightly decreases the overall flexibility of three alleles compared to the apo simulations. Fig 6c shows that the RMSDs stabilize at different rates, depending on the allele and frame. This variability is expected because the different peptides are expected to have different affinities to HLA and lapatinib. Fig 6d shows that the binding groove of the DRB1*07:01 trimer is notably narrower than other systems. In Fig 7, structural analyses of the trimer simulations are presented in three panels. The placement of a peptide lying over the bound lapatinib serves to reduce the mobility and flexibility of lapatinib except for the lapatinib-DRB1*01:01-frame 3 system. Thus, these systems appear more stable in the trimer form than the lapatinib-bound HLA simulations.


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)

Simulated structures of trimer-HLA system.HLA-DRB1*01:01-Frame 2 (a-c), HLA-DRB1*01:01-Frame 3 (d-f), HLA-DRB1*07:01 (g-i) and HLA-DRB1*15:01 (j-l). (a), (d), (g) and (j): Alignment of initial structure (red) and a representative structure (blue). (b), (e), (h) and (k): Sausage plot of the structure where the color and the thickness of HLA are proportional to the RMSF of α carbon. The color scales for the sausage plots are the same throughout this document. (c), (f), (i) and (l): The volume occupied by lapatinib and peptide. The blue envelope outlines the 50% occupancy volume of the drug (red) and peptide (green).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130928.g007: Simulated structures of trimer-HLA system.HLA-DRB1*01:01-Frame 2 (a-c), HLA-DRB1*01:01-Frame 3 (d-f), HLA-DRB1*07:01 (g-i) and HLA-DRB1*15:01 (j-l). (a), (d), (g) and (j): Alignment of initial structure (red) and a representative structure (blue). (b), (e), (h) and (k): Sausage plot of the structure where the color and the thickness of HLA are proportional to the RMSF of α carbon. The color scales for the sausage plots are the same throughout this document. (c), (f), (i) and (l): The volume occupied by lapatinib and peptide. The blue envelope outlines the 50% occupancy volume of the drug (red) and peptide (green).
Mentions: Each of the trimer simulations is energetically stable (Fig 6a). This is not unexpected because the trimer models were built from the output of the lapatinib-bound HLA and peptide-bound HLA simulations, which all contained stable HLA conformations by the end of the simulations. Although both lapatinib and peptide contribute a relatively small percent of the total system energy and thus their effect is not seen in the graph, the forces applied to each molecule through the MD simulation are still maintained and the compounds move accordingly. Therefore, while we see conformation changes in Fig 7, the energy plot can appear relatively flat. Fig 6b shows that the flexibility of the HLA molecule is very similar in all simulations. Overall, the presence of peptide and lapatinib slightly decreases the overall flexibility of three alleles compared to the apo simulations. Fig 6c shows that the RMSDs stabilize at different rates, depending on the allele and frame. This variability is expected because the different peptides are expected to have different affinities to HLA and lapatinib. Fig 6d shows that the binding groove of the DRB1*07:01 trimer is notably narrower than other systems. In Fig 7, structural analyses of the trimer simulations are presented in three panels. The placement of a peptide lying over the bound lapatinib serves to reduce the mobility and flexibility of lapatinib except for the lapatinib-DRB1*01:01-frame 3 system. Thus, these systems appear more stable in the trimer form than the lapatinib-bound HLA simulations.

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