In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01.
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.
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.
Makoto
M
Hirasawa
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.
Katsunobu
K
Hagihara
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.
Koji
K
Abe
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.
Osamu
O
Ando
Institute of Advanced Biosciences, Tokai University, 4-1-1 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan. tousa@tsc.u-tokai.ac.jp.
Noriaki
N
Hirayama
D001384:Azetidines / Q000737:chemistry / Q000378:metabolism*; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053719:Tandem Mass Spectrometry
D001384:Azetidines; D001596:Benzylamines; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen; D008024:Ligands; D010455:Peptides; C426686:ximelagatran
HLA (human leukocyte antigen); IDT (idiosyncratic drug toxicity); MD (molecular dynamics) simulation; hepatotoxicity; melagatran; ximelagatran