Unraveling the enigma: Probing the unconventional binding site and binding mechanism of entrectinib with human serum albumin through spectroscopic, molecular docking, and dynamic simulation analyses

•Static binding mechanism of ENB and HSA confirmed by fluorescence-based binding constants and quenching rate constants.•Thermodynamic analysis demonstrated a spontaneous interaction between ENB and HSA, primarily driven by electrostatic forces.•Near and far UV spectrophotometric analyses revealed t...

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Bibliographic Details
Published in:Journal of molecular liquids 2024-09, Vol.409, p.125447, Article 125447
Main Authors: Saber Abdelhameed, Ali, Bakheit, Ahmed H., Alanazi, Amer M., AlRabiah, Haitham
Format: Article
Language:English
Subjects:
Entrectinib
Fluorescence quenching
Human Serum Albumin
Ligand-protein interactions
NTRK gene fusion
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Summary:•Static binding mechanism of ENB and HSA confirmed by fluorescence-based binding constants and quenching rate constants.•Thermodynamic analysis demonstrated a spontaneous interaction between ENB and HSA, primarily driven by electrostatic forces.•Near and far UV spectrophotometric analyses revealed the development of ENB-HSA complex and suggested no structural variations in the protein.•Fluorescence measurements and binding competition analysis using site markers along with In-silico approaches revealed ENB binds in HSA Sudlow sites I and III with more favorable binding at site III. Entrectinib (ENB), a novel potent tyrosine kinase inhibitor, has demonstrated promising activity against specific genetic alterations in various solid tumors. Investigating the interaction of ENB with human serum albumin (HSA) provides valuable insights into its binding characteristics and pharmacological behavior. The interaction between ENB and HSA was investigated using various spectroscopic techniques, molecular docking, and simulations approaches. Fluorescence spectroscopy revealed a consistent decrease in the intrinsic fluorescence of HSA upon binding to ENB, indicating a static binding mechanism. The binding constant calculated from Stern Volmer and double-log equations (KSV) and (K) were determined to be 4.11 x104 M−1 and 4.38 x104 M−1, respectively at 298 K, indicating moderate binding affinity. Thermodynamic analysis demonstrated a spontaneous interaction (ΔG 
ISSN:0167-7322
DOI:10.1016/j.molliq.2024.125447