Unveiling the molecular interaction of hepatitis B virus inhibitor, entecavir with human serum albumin through computational, microscopic and spectroscopic approaches

Abstract

Molecular docking, molecular dynamics (MD) simulation, atomic force microscopy (AFM) and multi-spectroscopic techniques were selected to unveil the molecular association between the hepatitis B virus (HBV) inhibitor, entecavir (ETR), and the major blood plasma transporter, human serum albumin (HSA). The entire docking and simulation analyses recognized ETR binding to subdomain IIA (Site I) of HSA through hydrogen bonds, hydrophobic and van der Waals forces while maintaining the complex’s stability throughout the 100 ns. A gradual lessening in the Stern-Volmer quenching constant ($K_{\mathit{\text{sv}}}$) with rising temperatures registered ETR-induced quenching of HBV fluorescence as static quenching, thus advising complexation between ETR and HSA. The further advocation of this conclusion was seen from a larger value of the biomolecular quenching rate constant (($\mathit{\text{kq}}$) > 10¹⁰ M⁻¹s⁻¹), changes in the spectra (UV-Vis absorption) of HSA following ETR inclusion and ETR-induced swelling of HSA in the AFM results. The ETR appeared to bind to HSA with moderate affinity ($K_a=1.87-1.19\times {10}^4$M⁻¹) at 290, 300 and 310 K. Significant alterations in the protein’s secondary and tertiary structures, including changes in the protein’s Tyr/Trp microenvironment, were also detected by circular dichroism and three-dimensional fluorescence spectra when the protein was bound to ETR. The findings of the drug displacement study backed the docking results of Site I as ETR's preferred binding site in HSA.

Communicated by Ramaswamy H. Sarma

Keywords:

• Atomic force microscopy
• entecavir
• hepatitis B virus inhibitor
• human serum albumin
• molecular dynamics simulation

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Author’s contribution

Mujaheed Abubakar: Investigation, Writing—original draft. Saharuddin B. Mohamad: Conceptualization, Visualization, Supervision. Adyani Azizah Abd Halim: Conceptualization, Visualization. Saad Tayyab: Conceptualization, Visualization, Supervision and final draft.

Additional information

Funding

As a token of their gratitude, the authors would like to express their thanks for the support and resources offered by the Institut Sains Biologi, Universiti Malaya, which were important in the successful completion of this research. The author, M. A., would like to acknowledge the Tertiary Education Trust Fund, Nigeria (TETF/ES/UNIV/JIGAWA/TSAS/2020) for the scholarship offer.