Investigation of Atorvastatin interaction with human serum albumin: evaluation of pH effect and competitive binding with warfarin

Abstract

The current research used a fluorescence quenching titrations method combined with UV-Vis and FTIR-ATR spectroscopy to investigate the molecular mechanism of atorvastatin interaction with human serum albumin (HSA). Thermodynamic evaluations and molecular docking simulations were used to investigate the mode of atorvastatin-HSA interaction and the contributed intramolecular forces in complex stabilization. Atorvastatin is a statin anti-lipid drug that has recently sparked interest due to its growth-factor-like properties and other pharmacological functions, necessitating detailed knowledge of its molecular mechanism of action. UV-Vis spectra analysis confirmed the formation of the HSA-atorvastatin complex while fitting the fluorescence quenching titrations data to the proper models revealed that complex formation is facilitated by a combined static and dynamic mechanism with a quenching constant value (KSV) of 2.25×104 M-1 at 298 K. FTIR studies showed the variation of the secondary structure of the HSA due to the complex formation with atorvastatin. Based on the thermodynamic evaluations, the complex formation probability was increased due to the improved diffusion and miscibility or conformational change of HSA. Although hydrophobic interactions contribute to atorvastatin-HSA complex formation. Decreased binding was observed both in acidic and basic pHs, which could be a result of variation in the contribution of COOH moiety of atorvastatin in complex formation at different pH. Molecular docking simulations confirmed competitive binding of atorvastatin and warfarin to the site I of HSA. The docking results revealed that the flexibility of the atorvastatin molecular structure is critical in improving the stability of the atorvastatin-HSA complex.