ArticleJournal of medicinal chemistry2014
Targeting the GPIbα binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Detection of α-Thrombin with Platelet Glycoprotein Ibα (GP1bα) for the Development of a Coagulation Marker.ACS omega · 2024Article
- Merging cultures and disciplines to create a drug discovery ecosystem at Virginia commonwealth university: Medicinal chemistry, structural biology, molecular and behavioral pharmacology and computational chemistry.SLAS discovery : advancing life sciences R & D · 2023Review
- Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.Journal of medicinal chemistry · 2023Review
- Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for Various Pathologies.Current medicinal chemistry · 2020Review
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- Deciphering Conformational Changes Associated with the Maturation of Thrombin Anion Binding Exosite I.Biochemistry · 2017Article
- Article
- Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin.Scientific reports · 2016Article
- Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoprotein Ibα-binding and heparin-binding site of thrombin.Journal of thrombosis and haemostasis : JTH · 2016Article
- Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases.Molecules (Basel, Switzerland) · 2015Review
- Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin's active site through exosite 2.Biochemical and biophysical research communications · 2014Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 3 countries.
Funding
Abstract
Exosite 2 of human thrombin contributes to two opposing pathways, the anticoagulant pathway and the platelet aggregation pathway. We reasoned that an exosite 2 directed allosteric thrombin inhibitor should simultaneously induce anticoagulant and antiplatelet effects. To assess this, we synthesized SbO4L based on the sulfated tyrosine-containing sequence of GPIbα. SbO4L was synthesized in three simple steps in high yield and found to be a highly selective, direct inhibitor of thrombin. Michelis-Menten kinetic studies indicated a noncompetitive mechanism of inhibition. Competitive inhibition studies suggested ideal competition with heparin and glycoprotein Ibα, as predicted. Studies with site-directed mutants of thrombin indicated that SbO4L binds to Arg233, Lys235, and Lys236 of exosite 2. SbO4L prevented thrombin-mediated platelet activation and aggregation as expected on the basis of competition with GPIbα. SbO4L presents a novel paradigm of simultaneous dual anticoagulant and antiplatelet effects achieved through the GPIbα binding site of thrombin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.