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

Makoto Hirasawa, Katsunobu Hagihara, Koji Abe, Osamu Ando, Noriaki Hirayama

International journal of molecular sciences 2017 Mar 24

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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.

Citation

Makoto Hirasawa, Katsunobu Hagihara, Koji Abe, Osamu Ando, Noriaki Hirayama. In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01. International journal of molecular sciences. 2017 Mar 24;18(4)