Anticoagulant drug discovery
Warfarin has been used as an oral anti-coagulant since 1954 and prescribed as a racemic mixture, where 42 possible chemical entities (4 shown above) could be floating in the body. In spite of its complex pharmacokinetics and interactions, it still remains first drug of choice for pulmonary embolism (PE), deep vein thrombosis (DVT), atrial fibrillation, thrombosis and thromboembolism.
A combination of quantum mechanical and free energy calculations have been used to investigate the preference of a given tautomeric form in a given environment (vacuum, water, membrane, protein cavity) to facilitate the design of Warfarin derivatives to maximize the potency at the drug target (Vitamin K Epoxide Reductase) and minimize off-target interactions.
Partnership is welcome to translate the design into discovery of potential anticoagulants.