Vanderbilt Summer Science Academy

Development of a non-competitive antagonist for the Protease-Activated Receptor-4

Cardiac disease is the leading cause of death in the United States, and the current methods of treatment on the market are known to cause excess and sometimes fatal bleeding, such as Warfarin and Plavix.1 The Protease-Activated Receptors subtype 1 and 4, located on platelets, are responsible for the activation of clotting, the body’s response to excess bleeding. Targeting Protease-Activated Receptor-4 (PAR4) exclusively could allow for clotting while preventing thrombosis, or the formation of a blood clot. Because the protein crystal structure is not available, we use a homology modeling method in order to transition from a competitive molecular series to a noncompetitive molecular series. We intend to develop a series of molecules that have improved target binding to the PAR4 while maintaining potency and pharmacokinetic properties. We aim to use the homology model to drive structure activity relationship (SAR) with various organic chemistry methods, in order to develop a noncompetitive antagonist for PAR4. In developing this antiplatelet series of molecules the hope is that patients will no longer have to struggle with the negative side effects of the current therapeutics.