Binding characteristics of Bruton’s tyrosine kinase inhibitor ibrutinib with bovine serum albumin: multi-spectroscopic combined with molecular simulation

Abstract

Ibrutinib, as an oral Bruton’s tyrosine kinase inhibitor, has highly potent, covalent irreversible, and other characteristics. In this work, the binding characteristics of ibrutinib with bovine serum albumin were investigated using multi-spectroscopic techniques and molecular simulations. The findings demonstrated that ibrutinib could quench the endogenous fluorescence of bovine serum albumin by static quenching mode, meanwhile bovine serum albumin could also quench the fluorescence of ibrutinib. In the binding process of ibrutinib with bovine serum albumin, ibrutinib caused a bathochromic shift in the absorption band of bovine serum albumin, further indicating that ibrutinib and bovine serum albumin formed a ground state ibrutinib and bovine serum albumin complex. It is confirmed that ibrutinib has a strong affinity to bovine serum albumin due to the binding constant of more 104 M−1. Experimental findings showed that ibrutinib resulted in the decrease in the hydrophobicity or the enhancement in the polarity of the surroundings around Tyr and Trp residues of bovine serum albumin and diminishing in α-helix and β-sheet content of bovine serum albumin. The findings from site-competition experiments confirmed that the binding site of ibrutinib onto bovine serum albumin was the same as that of ibuprofen, that is, ibrutinib bound to the site II' site of bovine serum albumin, which was verified by molecular docking. The findings from thermodynamic analysis revealed that ibrutinib spontaneously bound onto bovine serum albumin through an enthalpy-driven and the driving forces included hydrogen bonding and van der Waals forces being the dominating forces. The findings from molecular dynamics simulation confirmed that some residues such as ARG-208, ALA-209, ALA-212, LEU-326, and LYS-350 made major contributions in ibrutinib and bovine serum albumin complexation.