Protein-drug interaction is of prominent interest in determining the pharmacokinetic and pharmacodynamic consequences on drug delivery. Warfarin is a widely used anticoagulant drug in the treatment of venous thrombosis and pulmonary embolism and is carried in the blood almost exclusively by human serum albumin. The effects of the binding of warfarin to the native state of albumin were characterized by UV–vis absorption, conventional and synchronous fluorescence, isothermal titration calorimetry, differential scanning calorimetry and molecular dynamics simulation. The overall results indicate that, under physiological condition, the binding of warfarin in site DS1 of albumin promotes local stabilization with resulting effects on the global protein dynamics. The increase of the protein stability has both an enthalpic and entropic character. Under denaturing condition, the stabilizing effect of warfarin is evidenced by an increase of both the melting temperature and unfolding enthalpy of albumin with the drug/protein molar ratio. More importantly, thermal resistance is increased due to selective effect on the specific protein lobe that includes the main drug binding site. The comparison of the thermal behavior of the protein-warfarin complex with that in the presence of a typical ligand of the other main protein binding site, i.e. drug site DS2, provides key insight on domain-specific stabilization effects on albumin.
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