title: Discovery of novel GPVI receptor antagonists by structure-based repurposing.
abstract: Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing.
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, United Kingdom.
authors: Lewis
authors: L
authors: Taylor
authors: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, United Kingdom.
authors: Sridhar R
authors: SR
authors: Vasudevan
authors: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Hopkins Building, Reading, United Kingdom.
authors: Chris I
authors: CI
authors: Jones
authors: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Hopkins Building, Reading, United Kingdom.
authors: Jonathan M
authors: JM
authors: Gibbins
authors: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, United Kingdom.
authors: Grant C
authors: GC
authors: Churchill
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, United Kingdom.
authors: R Duncan
authors: RD
authors: Campbell
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford, United Kingdom.
authors: Carmen H
authors: CH
authors: Coxon
mesh_terms: D000595:Amino Acid Sequence; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D002928:Cinanserin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019808:Losartan / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D010980:Platelet Membrane Glycoproteins; D054852:Small Molecule Libraries; C098341:platelet membrane glycoprotein VI; D019808:Losartan; D002928:Cinanserin