Natural sapogenins as potential inhibitors of aquaporins for targeted cancer therapy: computational insights into binding and inhibition mechanism

Abstract

Aquaporins (AQPs) are membrane proteins that facilitate the transport of water and other small molecules across biological membranes. AQPs are involved in various physiological processes and pathological conditions, including cancer, making them as potential targets for anticancer therapy. However, the development of selective and effective inhibitors of AQPs remains a challenge. In this study, we explored the possibility of using natural sapogenins, a class of plant-derived aglycones of saponins with diverse biological activities, as potential inhibitors of AQPs. We performed molecular docking, dynamics simulation and binding energy calculation to investigate the binding and inhibition mechanism of 19 sapogenins against 13 AQPs (AQP0-AQP13) that are overexpressed in various cancers. Our results showed that out of 19 sapogenins, 8 (Diosgenin, Gitogenin, Tigogenin, Ruscogenin, Yamogenin, Hecogenin, Sarsasapogenin and Smilagenin) exhibited acceptable drug-like characteristics. These sapogenin also exhibited favourable binding affinities in the range of −7.6 to −13.4 kcal/mol, and interactions within the AQP binding sites. Furthermore, MD simulations provided insights into stability and dynamics of the sapogenin-AQP complexes. Most of the fluctuations in binding pocket were observed for AQP0-Gitogenin and AQP4-Diosgenin. However, remaining protein–ligand complex showed stable root mean square deviation (RMSD) plots, strong hydrogen bonding interactions, stable solvent-accessible surface area (SASA) values and minimum distance to the receptor. These observations suggest that natural sapogenin hold promise as novel inhibitors of AQPs, offering a basis for the development of innovative therapeutic agents for cancer treatment. However, further validation of the identified compounds through experiments is essential for translating these findings into therapeutic applications.

Communicated by Ramaswamy H. Sarma

Keywords:

• Aquaporins
• sapogenins
• membrane proteins
• cancer therapy
• molecular dynamics

Acknowledgement

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number RI-44-0848.

Author's contribution

Modhi O. Alotaibi: Conceptualization, Writing- Original draft preparation, Data curation, Investigation, Methodology, Nahaa M. Alotaibi: Formal analysis, Validation, Visualization, Writing- review and editing, Maha Abdullah Alwaili: Formal analysis, Investigation and validation, Nawaf Alshammari: Formal analysis, Investigation and validation, Mohd Adnan: Data curation, Validation, Writing- review and editing, Mitesh Patel: Conceptualization, Project administration, Formal analysis, Methodology, Writing- review and editing.

Data availability statement

All data generated or analyzed during this study are included in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work is supported by the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia through the project number RI-44-0848.