Toward α-1,3/4 fucosyltransferases targeted drug discovery: In silico uncovering of promising natural inhibitors of fucosyltransferase 6.

Jorge Samuel Leon Magdaleno, Ravneet Kaur Grewal, José L Medina-Franco, Romina Oliva, Abdul Rajjak Shaikh, Luigi Cavallo, Mohit Chawla

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Sialyl Lewis X (sLex) antigen is a fucosylated cell-surface glycan that is normally involved in cell-cell interactions. The enhanced expression of sLex on cell surface glycans, which is attributed to the upregulation of fucosyltransferase 6 (FUT6), has been implicated in facilitating metastasis in human colorectal, lung, prostate, and oral cancers. The role that the upregulated FUT6 plays in the progression of tumor to malignancy, with reduced survival rates, makes it a potential target for anticancer drugs. Unfortunately, the lack of experimental structures for FUT6 has hampered the design and development of its inhibitors. In this study, we used in silico techniques to identify potential FUT6 inhibitors. We first modeled the three-dimensional structure of human FUT6 using AlphaFold. Then, we screened the natural compound libraries from the COCONUT database to sort out potential natural products (NPs) with best affinity toward the FUT6 model. As a result of these simulations, we identified three NPs for which we predicted binding affinities and interaction patterns quite similar to those we calculated for two experimentally tested FUT6 inhibitors, that is, fucose mimetic-1 and a GDP-triazole derived compound. We also performed molecular dynamics (MD) simulations for the FUT6 complexes with identified NPs, to investigate their stability. Analysis of the MD simulations showed that the identified NPs establish stable contacts with FUT6 under dynamics conditions. On these grounds, the three screened compounds appear as promising natural alternatives to experimentally tested FUT6 synthetic inhibitors, with expected comparable binding affinity. This envisages good prospects for future experimental validation toward FUT6 inhibition.
Original languageEnglish (US)
JournalJournal of Cellular Biochemistry
StatePublished - Jun 25 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-07-13
Acknowledgements: Luigi Cavallo and Mohit Chawla acknowledge the KAUST Core Labs and Supercomputing Laboratory for providing computational resources on the HPC platform Shaheen II. Team members from STEMskills Research and Education Lab Private Limited are acknowledged for the critical reading of manuscript and computational support. The research carried out was supported by King Abdullah University of Science and Technology: BAS funding to Luigi Cavallo. Romina Oliva would like to thank MIUR-FFABR “Fondo per il Finanziamento Attività Base di Ricerca” for funding.

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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