Search for Antithrombotic Compounds to Overcome Adverse Effects of Current Drugs

DESCRIPTION (provided by applicant): Uncontrolled blood clotting or thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the western world: heart attacks, stroke and ca ncer. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects leading to emergency room treatment of patients. Our goal is to develop new anti- thrombotic drugs that overcome the limitations o f current marketed drugs. Our molecular target is Factor XIa (FXIa), a serine protease that plays a key role in the amplification of the blood coagulation cascade. To that end, we will integrate virtual (computer) screening methods and biochemical assays t o identify lead compounds that can potentially be optimized to produce novel drugs for the treatment of thrombosis. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way t o screen million of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of the FXIa catalytic domain makes this work possible. The specific aims of this work are to: 1. Use virt ual screening methods to identify compounds that bind in the FXIa active site. 2. Determine the ability of the selected compounds to inhibit FXIa activity in an in vitro assay. 3. Confirm the activity of the selected compounds determined in Specific Aim 2 using plasma or blood-based in vitro assay systems. PUBLIC HEALTH RELEVANCE: Uncontrolled blood clotting or thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the wes tern world: heart attacks, stroke and cancer. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects leading to emergency room treatment of patients. Our goal is to develop new drugs that ove rcome the limitations of current marketed drugs.