Exploring the binding characteristics of bovine serum albumin with CDK4/6 inhibitors Ribociclib: Multi-spectral
Shao-Liang Jiang1, Wang-Cai Chen1, Yu-Ting Wu1
1College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou 310032, China.
Abstract:
Ribociclib (RIB), a tyrosine kinase inhibitor, exhibits promising antitumor efficacy and controlled toxicity in HR+/HER2- breast cancer patients, which is closely related to the binding with plasma proteins. This study utilized a combination of spectroscopic techniques including UV spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) as well as molecular docking and molecular dynamic simulation to clarify the binding mechanism between bovine serum albumin (BSA) and RIB. The findings demonstrated that RIB produced a 1:1 stoichiometric complex with BSA, which quenched BSA's fluorescence in the manner of the static quenching mechanism. Site labelling experiments pinpointed Site III on BSA as the primary binding site for RIB, a finding validated by molecular docking. Van der Waals forces and hydrogen bonding interactions as key drivers in the formation of RIB-BSA complexes, a conclusion supported by molecular docking. Molecular simulation studies suggested that the insertion of RIB into the hydrophobic cavity (Site III) of BSA induced subtle conformational changes in the BSA protein, and CD measurements confirmed alterations in BSA secondary structure content. Synchronous and three-dimensional fluorescence spectroscopy further demonstrated that RIB decreased the hydrophobicity of the microenvironment surrounding tyrosine and tryptophan residues. These findings offer valuable insights into the pharmacokinetics and structural modifications of RIB.
Insights
This study reveals how Ribociclib (RIB) binds to bovine serum albumin (BSA), showing a 1:1 complex formation at Site III. These interactions, driven by Van der Waals forces and hydrogen bonding, alter BSA structure and hydrophobicity, impacting RIB pharmacokinetics.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Ribociclib (RIB) is a tyrosine kinase inhibitor used for HR+/HER2- breast cancer.
- RIB's efficacy and toxicity are influenced by its binding to plasma proteins like bovine serum albumin (BSA).
- Understanding RIB-BSA interactions is crucial for optimizing its pharmacokinetic profile.
Purpose of the Study:
- To elucidate the binding mechanism between Ribociclib (RIB) and bovine serum albumin (BSA).
- To identify the binding site and forces involved in RIB-BSA complex formation.
- To investigate the structural and microenvironmental changes in BSA upon RIB binding.
Main Methods:
- Spectroscopic techniques: UV-Vis spectroscopy, fluorescence spectroscopy, circular dichroism (CD).
- Computational methods: Molecular docking and molecular dynamic simulations.
- Site-specific labeling experiments.
Main Results:
- RIB forms a 1:1 stoichiometric complex with BSA via static quenching of BSA fluorescence.
- RIB primarily binds to Site III on BSA, involving Van der Waals forces and hydrogen bonding.
- RIB binding induces conformational changes in BSA, affecting its secondary structure and decreasing hydrophobicity around tyrosine and tryptophan residues.
Conclusions:
- The binding of RIB to BSA is characterized by a specific stoichiometry and site preference.
- The interaction involves non-covalent forces and leads to significant structural alterations in BSA.
- These findings provide critical insights into the pharmacokinetics and drug-protein interactions of Ribociclib.
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