Molecular interaction study of flavonoid derivative 3d with human serum albumin using multispectroscopic and molecular modeling approach

• The interaction of HSA with a flavonoid derivative (3d) we designed was investigated.
• 3d can bind to HSA with high affinity and it can be transported and deposited by HSA.
• Molecular modeling showed that 3d can enter into a hydrophobic cavity of HSA at its subdomain IIA.
• The conformation of HSA changed due to the formation of 3d–HSA complex.

Human serum albumin (HSA) has been developed as a model protein to study drug–protein interaction. In the present work, the interaction between our synthesized flavonoid derivative 3d (possessing potent antitumor activity against HepG2 cells) and HSA was investigated using fluorescence spectroscopy, circular dichroism spectroscopy, UV–vis spectroscopy and molecular modeling approach. Fluorescence spectroscopy showed that the fluorescence of HSA can be quenched remarkably by 3d under physiological condition with a slight shift of maximum fluorescence emission bands from 360 nm to 363 nm. Calculated results from Stern–Volmer equation and modified Stern–Volmer equation indicated that the fluorescence was quenched by static quenching processing with association constant 5.26±0.04×104 L mol−1 at 298 K. After comprehensive consideration of the free energy change ΔG, enthalpy change ΔH and entropy change ΔS, electrostatic interactions were confirmed as the main factor that participate in stabilizing the 3d–HSA complex. Both dichroism spectroscopy and UV–vis spectroscopy indicated conformational change of HSA after binding to 3d. Moreover, the structure of HSA was loosened and the percentage of α-helix decreased with increasing concentration of 3d. Molecular modeling results demonstrated that 3d could bind to HSA well into subdomain IIA, which is related to its capability of deposition and delivery. Three cation–π interactions and three hydrogen bonds occurred between 3d and amino acid residuals ARG218, ARG222 and LYS199. In conclusion, flavonoid derivative 3d can bind to HSA with noncovalent bond in a relatively stable way, so it can be delivered by HSA in a circulatory system.

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