期刊
PHARMACEUTICS
卷 13, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13040524
关键词
ticagrelor; P2Y(12) receptors; platelets; molecular dynamics
资金
- NATO Science for Peace and Security Programme [SPS 985291]
- European Union's Horizon 2020 research and Innovation Programme under the Marie Sklodowska-Curie grant [796245]
- Marie Curie Actions (MSCA) [796245] Funding Source: Marie Curie Actions (MSCA)
This study investigated the mechanism of binding between the P2Y12 receptor and different ligands through molecular dynamics simulations and ensemble docking, revealing that internal protein dynamics and membrane environment play a crucial role in ligand binding.
The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y(12) receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP) and 2-Methylthioadenosine diphosphate (2MeS-ADP) as agonist, and ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate (AZD1283)as antagonist were assessed systematically by means of ensemble docking. It is shown that the binding of all ligands becomes systematically stronger with the increase of the membrane rigidity. Binding of all ligands to the agonist-bound-like conformations is systematically stronger in comparison to antagonist-bound-likes ones. This is dramatically opposite to the results obtained for static crystal structures. Our results show that accounting for internal protein dynamics, strongly modulated by its lipid environment, is crucial for correct assessment of the ligand binding to P2Y12.
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