PMID- 28338626
OWN - NLM
STAT- MEDLINE
DCOM- 20170426
LR  - 20181113
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 18
IP  - 4
DP  - 2017 Mar 24
TI  - In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human 
      Leukocyte Antigen (HLA)-DRB1*07:01.
LID - 10.3390/ijms18040694 [doi]
LID - 694
AB  - Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be 
      associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has 
      been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in 
      vitro. In order to predict the possible interaction modes of ximelagatran with 
      HLA-DR molecules, in silico docking simulations were performed. Molecular 
      dynamics (MD) simulations were also performed to predict the effect of 
      ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01. A 
      series of in silico simulations supported the inhibitory effect of ximelagatran 
      on the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. Furthermore, 
      direct interactions of ximelagatran with HLA-DR molecules were evaluated in 
      vitro, which supported the simulated interaction mode of ximelagatran with 
      HLA-DRB1*07:01. These results indicated that ximelagatran directly interacts with 
      the peptide binding groove of HLA-DRB1*07:01 and competes with the ligand peptide 
      for the binding site, which could alter the immune response and lead to the 
      idiosyncratic ximelagatran-induced hepatotoxicity.
FAU - Hirasawa, Makoto
AU  - Hirasawa M
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      hirasawa.makoto.n4@daiichisankyo.co.jp.
FAU - Hagihara, Katsunobu
AU  - Hagihara K
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      hagihara.katsunobu.fc@daiichisankyo.co.jp.
FAU - Abe, Koji
AU  - Abe K
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      abe.koji.ce@daiichisankyo.co.jp.
FAU - Ando, Osamu
AU  - Ando O
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      ando.osamu.jy@daiichisankyo.co.jp.
FAU - Hirayama, Noriaki
AU  - Hirayama N
AD  - Institute of Advanced Biosciences, Tokai University, 4-1-1 Kitakaname, 
      Hiratsuka-shi, Kanagawa 259-1292, Japan. tousa@tsc.u-tokai.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20170324
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Azetidines)
RN  - 0 (Benzylamines)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*07 antigen)
RN  - 0 (Ligands)
RN  - 0 (Peptides)
RN  - 49HFB70472 (ximelagatran)
SB  - IM
MH  - Azetidines/chemistry/*metabolism
MH  - Benzylamines/chemistry/*metabolism
MH  - Binding Sites
MH  - Chromatography, High Pressure Liquid
MH  - HLA-DRB1 Chains/chemistry/*metabolism
MH  - Humans
MH  - Ligands
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Peptides/chemistry/metabolism
MH  - Protein Structure, Tertiary
MH  - Tandem Mass Spectrometry
PMC - PMC5412280
OTO - NOTNLM
OT  - HLA (human leukocyte antigen)
OT  - IDT (idiosyncratic drug toxicity)
OT  - MD (molecular dynamics) simulation
OT  - hepatotoxicity
OT  - melagatran
OT  - ximelagatran
COIS- The authors declare no conflict of interest.
EDAT- 2017/03/25 06:00
MHDA- 2017/04/27 06:00
PMCR- 2017/04/01
CRDT- 2017/03/25 06:00
PHST- 2017/02/20 00:00 [received]
PHST- 2017/03/21 00:00 [revised]
PHST- 2017/03/21 00:00 [accepted]
PHST- 2017/03/25 06:00 [entrez]
PHST- 2017/03/25 06:00 [pubmed]
PHST- 2017/04/27 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - ijms18040694 [pii]
AID - ijms-18-00694 [pii]
AID - 10.3390/ijms18040694 [doi]
PST - epublish
SO  - Int J Mol Sci. 2017 Mar 24;18(4):694. doi: 10.3390/ijms18040694.