Drug repurposing against fucosyltransferase-2 via docking, STD-NMR, and molecular dynamic simulation studies

Muhammad Atif ¹, Humaira Zafar ², Atia-Tul- Wahab ²

⁰International Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of Karachi, Karachi, Pakistan.

Plos One +

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November 1, 2024

View abstract on PubMed

Summary

Aberrant fucosylation drives cancer progression. This study repurposed FDA-approved drugs, identifying four potential inhibitors, including acarbose and ibuprofen, targeting fucosyltransferase 2 (FUT2) for cancer therapy.

Area Of Science

Biochemistry
Cancer Biology
Drug Discovery

Background

Aberrant fucosylation is a key feature of cancer, promoting tumor growth, invasion, and metastasis.
Fucosyltransferases (FUTs) catalyze fucose addition, and their overexpression is linked to malignancy, making them validated cancer drug targets.
Fucosyltransferase 2 (FUT2) is implicated in cancer development.

Purpose Of The Study

To identify potential cancer therapeutics by repurposing existing drugs against fucosyltransferase 2 (FUT2).
To utilize computational and biophysical methods for drug screening and validation.

Main Methods

In-silico screening of 500 US-FDA approved drugs against FUT2 donor and acceptor sites.
Molecular docking and binding energy calculations to predict drug efficacy.
Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) to identify drug binding epitopes.
Molecular simulation studies to elucidate drug-binding site interactions.

Main Results

Five drugs showed significant docking scores (-5.8 to -8.2) and binding energies (-43 to -51.19 Kcal/mol) against FUT2.
STD-NMR confirmed drug binding within the FUT2 active site.
Acarbose, ascorbic acid, ibuprofen, and enalaprilat dihydrate were identified as significant binders at the FUT2 donor binding site.

Conclusions

The study successfully identified four repurposed drugs (acarbose, ascorbic acid, ibuprofen, enalaprilat dihydrate) as potential inhibitors of FUT2.
These findings offer a promising starting point for developing novel cancer therapies targeting aberrant fucosylation.