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Open AccessArticle

In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01

1
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
2
Institute of Advanced Biosciences, Tokai University, 4-1-1 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Rolf Teschke
Int. J. Mol. Sci. 2017, 18(4), 694; https://doi.org/10.3390/ijms18040694
Received: 20 February 2017 / Revised: 21 March 2017 / Accepted: 21 March 2017 / Published: 24 March 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
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. View Full-Text
Keywords: ximelagatran; melagatran; HLA (human leukocyte antigen); hepatotoxicity; IDT (idiosyncratic drug toxicity); MD (molecular dynamics) simulation ximelagatran; melagatran; HLA (human leukocyte antigen); hepatotoxicity; IDT (idiosyncratic drug toxicity); MD (molecular dynamics) simulation
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Hirasawa, M.; Hagihara, K.; Abe, K.; Ando, O.; Hirayama, N. In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01. Int. J. Mol. Sci. 2017, 18, 694.

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