Multispectral and molecular simulation of the interaction of human α1-acid glycoprotein with palbociclib

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 11; p. 130712
• Main Authors: Jiang, Shao-Liang, Wu, Yu-Ting, Chen, Wang-Cai, Huang, Jia-Ping, Chen, Dong, Li, Li, Han, Liang, Shi, Jie-Hua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2024
• Subjects: Binding Sites; Fluorescence spectroscopy; Human α-1-acid glycoprotein (HAG); Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Interaction mechanism; Molecular Docking Simulation; Molecular Dynamics Simulation; Orosomucoid - chemistry; Orosomucoid - metabolism; Palbociclib; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Protein Binding; Pyridines - chemistry; Pyridines - pharmacology; Human α-1-acid glycoprotein (HAG); Fluorescence spectroscopy; Interaction mechanism; Molecular dynamics simulation; Palbociclib
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130712

Palbociclib, a selective CDK4/6 inhibitor with potent anti-tumor effects, was investigated for its interaction with human α1-acid glycoprotein (HAG). Spectral analysis revealed that palbociclib forms a ground state complex with HAG, exhibiting binding constant (Kb) of 104 M−1 at the used temperature range. The interaction between the two was determined to be driven mainly by hydrogen bonding and hydrophobic forces. Multispectral studies indicated that the bound palbociclib altered the secondary structure of HAG and reduced polarity around Trp and Tyr amino acids. And, molecular docking and dynamics simulations verified the experimental findings. Finally, most of the metal ions present in plasma, such as K+, Cu2+, Ca2+, Mg2+, Ni2+, Fe3+, and Co2+, are detrimental to the binding of palbociclib to HAG, with the exception of Zn2+, which is favorable. •An intermolecular interaction of palbociclib with HAG was summarized.•Palbociclib quenches the intrinsic fluorescence of HAG in a static manner, forming a 1:1 complex.•Among the common metal ions, only Zn2+ favors the complex formation.•Palbociclib binds to HAG mainly through hydrogen bonding, hydrophobic forces and van der Waals forces.