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

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

doi:10.3390/ijms18040694

Makoto Hirasawa, Koji Abe + Show 3 more

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https://doi.org/10.3390/ijms18040694

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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.

Highlights

Idiosyncratic drug toxicity (IDT) is a rare toxic drug reaction characterized by the delayed onset of symptoms, a dose- and duration-independent occurrence, and an unpredictable nature
The lowest GBVI/WSA_dG values of complexes between ximelagatran or melagatran and and the the three molecules areare shown in the complexes between ximelagatran or melagatran three
The first docking studies indicated that ximelagatran and its active metabolite, melagatran, have high potential to interact with the peptide binding groove of human leukocyte antigen (HLA) molecules compared with other IDT causing drugs, nevirapine [12] and allopurinol [13]

Summary

Introduction

Idiosyncratic drug toxicity (IDT) is a rare toxic drug reaction characterized by the delayed onset of symptoms, a dose- and duration-independent occurrence, and an unpredictable nature. It is often life-threatening and, one of the major reasons for drug withdrawals or black box warnings. Ximelagatran was generally well tolerated in short-term use (3× upper limit of normal was found to develop during long-term treatment (>35 days) in 7.9% of patients [2]. A retrospective case-control pharmacogenetic study of ALT elevation during long-term treatment of ximelagatran revealed a strong genetic association between elevated ALT and the HLA alleles DRB1*07

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