Binding investigation of Ribociclib to human α-1-acid glycoprotein with spectroscopic and computational simulation approaches

Ribociclib, a selective small-molecule CDK4/6 inhibitor, was approved by the US FDA in 2017. It is administered in combination with endocrine therapy to treat advanced or metastatic HR+/HER2-breast cancer in premenopausal, perimenopausal, and postmenopausal women. The interaction of Ribociclib with human α-1-acid glycoprotein (HAG) was investigated through multi-spectroscopic techniques and molecular simulation approaches to elucidate its pharmacokinetic and pharmacodynamic properties. The results show that Ribociclib binds to HAG and forms a 1:1 complex, leading to the fluorescence quenching of HAG. Van der Waals forces, hydrogen bonds, and hydrophobic interactions dominate the binding of Ribociclib to HAG, as indicated by thermodynamic data and competition experiments. This conclusion is further corroborated by molecular docking simulations. The binding of Ribociclib induces a subtle conformational change in HAG, as revealed by molecular dynamics simulation and circular dichroism (CD) measurements. The observed redshift in the 3D fluorescence spectra suggests increased hydrophilicity of the microenvironment around the HAG binding sites. In addition, several common metal ions reduce the affinity of Ribociclib to HAG, as shown by a decrease in the binding constants. These findings provide valuable insight into Ribociclib's mechanism of action and could guide future structural optimization to enhance its therapeutic profile.