Differential scanning calorimetric domain dissection for HSA upon interaction with Bortezomib: Unveiling the binding dynamics.

Human serum albumin (HSA), a crucial plasma protein, plays a significant role in drug interactions within the bloodstream, bearing considerable clinical relevance. Bortezomib (BTZ) is a potent anti-cancer drug for multiple myeloma (MM) and mantle cell lymphoma (MC). The mechanism of BTZ transfer in the blood remains undetermined. This study aims to investigate the binding of BTZ to HSA using the techniques of differential scanning calorimetry (DSC), circular dichroism (CD), fluorescence spectroscopy, and computational methods such as molecular docking and molecular dynamics simulations. This study presents the thermal dissection of domain I (D I) of HSA by subjecting it to a temperature elevation of 79.2 °C (2 °C above T m of D I) using DSC, which provides new information on the thermal behavior of HSA domains. Furthermore, the deconvolution analysis of the HSA thermogram in the absence and presence of BTZ revealed that the drug binding site is located in D I and impacts D II. The interaction between BTZ and HSA with a binding affinity (K b) of 7.744±0.2 ×105 M−1 influences protein dynamics and reduces HSA's thermal stability by almost 1 °C. This study is crucial for predicting the pharmacokinetics and pharmacodynamics of BTZ, aiding in developing safer and more effective treatments for MM and MC. [Display omitted] • D II and D III domains of HSA have irreversible and D I has reversible denaturation at 79.2 °C. • BTZ binding site is located in the hydrophobic pocket of D I (subdomain IA). • The dissection of energetic domains of HSA-BTZ was done via DSC thermogram deconvolution. [ABSTRACT FROM AUTHOR]