Abstract
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.