Deciphering the binding mechanism of gingerol molecules with plasma proteins: implications for drug delivery and therapeutic potential

Abstract

Ginger is a highly valued herb, renowned globally for its rich content of phenolic compounds. It has been traditionally used to treat various health conditions such as cardiovascular diseases, digestive issues, migraines, Alzheimer’s disease, tumor reduction and chronic inflammation. Despite its potential medicinal applications, the therapeutic effectiveness of ginger is hindered by its limited availability and low plasma concentration levels. In this study, we explored the interaction of ginger’s primary phenolic compounds, specifically 6-gingerol (6 G), 8-gingerol (8 G) and 10-gingerol (10 G), with plasma proteins which are human serum albumin (HSA) and α-1-acid glycoprotein (AGP). These two plasma proteins significantly influence drug distribution and disposition as they are key binding sites for most drugs. Fluorescence emission spectra indicated strong binding of 6, 8 and 10 G with HSA, with binding constants of 2.03 ± 0.01 × 10⁴ M⁻¹, 4.20 ± 0.01 × 10⁴ M⁻¹ and 6.03 ± 0.01 × 10⁶ M⁻¹, respectively. However, the binding of gingerols with AGP was found to be negligible. Molecular displacement by site-specific probes and molecular docking analyses revealed that gingerols bind at the IIA domain, with stability provided by hydrogen bonds, van der Waals forces, conventional hydrogen bonds, carbon-hydrogen bonds, alkyl and Pi–alkyl interactions. Further, the partial unfolding of the protein was observed upon binding the gingerol compound with HSA. In addition, molecular dynamic simulations demonstrated that gingerols remained stable in the subdomain IIA over 100 ns. This stability, coupled with Molecular Mechanics Generalized Born Surface Area indicating free energies of −43.765, −57.504 and −66.69 kcal/mol for 6, 8 and 10 G, respectively, reinforces the robust binding potential of these compounds. Circular dichroism studies suggested that the interaction of gingerols leads to the minimal transformation of HSA secondary structure, with the pattern being 10 G > 8 G > 6 G, a finding further substantiated by root mean square deviation and root mean square fluctuation fluctuations. These results propose that HSA has a stronger affinity to gingerols than AGP, which could have significant implications on the therapeutic circulating levels of gingerols.

Communicated by Ramaswamy H. Sarma

Keywords:

• Gingerol molecules
• human serum albumin
• binding analysis
• fluorescence quenching
• molecular dynamics and simulations

Acknowledgments

We thank Bioinformatics facilities, University of Hyderabad.

Author contributions

MG carried out the experiments, analyzed the data and drafted the manuscript. MYZ and VSL have conducted experiments and analyzed the data. RS designed the experiments, drafted the manuscript and secured the fund. All authors approved the final version before submission.

Statement of informed consent, human/animal rights

No conflicts, informed consent, human or animal rights are applicable.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Science and Engineering Research Board (SB/EMEQ-064/2014 dated 14-07-2015 and DST-FIST), DST-FIST, DBT-Builder (BT/INF/22/SP41176/2020), UGC-SAP, UPE-2, Institute of Eminence, University of Hyderabad.