期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 12, 页码 9461-9472出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.311431
关键词
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资金
- Katholieke Universiteit Leuven [IOF-KP 06/001]
The von Willebrand factor (VWF) A1-glycoprotein (GP) Ib alpha interaction is of major importance during thrombosis mainly at sites of high shear stress. Inhibitors of this interaction prevent platelet-dependent thrombus formation in vivo, without major bleeding complications. However, the size and/or protein nature of the inhibitors currently in development limit oral bioavailability and clinical development. We therefore aimed to search for a small molecule protein-protein interaction inhibitor interfering with the VWF-GPIb alpha binding. After determination of putative small molecule binding pockets on the surface of VWF-A1 and GPIb alpha using site-finding algorithms and molecular dynamics, high throughput molecular docking was performed on both binding partners. A selection of compounds showing good in silico docking scores into the predicted pockets was retained for testing their in vitro effect on VWF-GPIb alpha complex formation, by which we identified a compound that surprisingly stimulated the VWF-GPIb alpha binding in a ristocetin cofactor ELISA and increased platelet adhesion in whole blood to collagen under arterial shear rate but in contrast inhibited ristocetin-induced platelet aggregation. The selected compound adhering to the predicted binding partner GPIb alpha could be confirmed by saturation transfer difference NMR spectroscopy. We thus clearly identified a small molecule that modulates VWF-GPIb alpha binding and that will now serve as a starting point for further studies and chemical modifications to fully characterize the interaction and to manipulate specific activity of the compound.
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