Key result
Molecular dynamics simulations revealed that the switchable conformation of losartan's C-N bond may explain its low activity against GPVI, providing insights for novel GPVI inhibitor design.
Why the study?
GPVI is a promising antithrombotic target with low bleeding risk, motivating investigation into the binding mode of the known GPVI inhibitor losartan.
Molecular dynamics simulations reveal the dominant conformation of losartan binding to GPVI, providing insights for designing novel GPVI inhibitors.
Glycoprotein VI (GPVI) plays an important role in platelet aggregation, and inhibition of GPVI may block thrombosis with a low bleeding risk, thus making GPVI a promising antithrombotic target. In this paper, the binding mode of losartan, a known GPVI inhibitor, was investigated using molecular docking and molecular dynamics methods as well. Docking results can determine the location site of the phenyl tetrazole group of losartan, but the direction of the two substitute groups on imidazole ring is uncertain. Therefore, two sample conformations were selected, and long-time molecular dynamics simulations were carried out. The rotatable bond of C–N connecting the imidazole ring and the middle benzene ring was monitored during the simulation. The results showed that this dihedral angle is mostly distributed at about [Formula: see text] for both systems, implying that this conformation is the dominant conformation. The switchable conformation may be the reason for low activity of losartan to GPVI. Losartan1 system was well equilibrated and selected as the receptor to perform drug repurposing screening, and several drugs with a similar binding mode as losartan were identified. Our study may enhance the mechanism understanding of GPVI receptor, giving insights into the design and discovery of novel GPVI inhibitors.
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Zheng et al. (2021) studied this question. Losartan was evaluated on Binding mode and conformation of losartan upon GPVI. Molecular dynamics simulations revealed that the switchable conformation of losartan's C-N bond may explain its low activity against GPVI, providing insights for novel GPVI inhibitor design.
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