Inhibitor screening identifies Entecavir as a promising candidate targeting human eIF4E to block cap-dependent...

Eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in cap-dependent translation by binding the 7-methylguanosine (m⁷G) cap at the 5' end of mRNAs, thereby regulating the synthesis of proteins essential for cell growth, survival, and proliferation. Under homeostatic conditions, eIF4E selectively translates a subset of mRNAs; however, in cancer, aberrant signaling leads to persistent activation of eIF4E, promoting tumor progression, metastasis, and resistance to therapy. Despite its clinical relevance, very few studies have explored direct targeting of eIF4E's cap-binding function using small molecules as a therapeutic strategy. In the present study, we adopted a multi-layered in silico and experimental pipeline to identify small-molecule inhibitors that can effectively disrupt human eIF4E activity. A library of over 400,000 compounds from the ZINC database was virtually screened using the Glide docking protocol in Schrödinger-Maestro. Compounds were shortlisted based on binding affinity and drug-likeness properties. Among the top hits, ZINC145267992, a nucleoside-like molecule, showed promising interaction with the cap-binding pocket of eIF4E. To overcome potential druggability limitations and improve clinical relevance, Entecavir (ETV), a clinically approved antiviral drug for hepatitis B and a structural analogue of ZINC145267992, was identified as a candidate for drug repurposing. Molecular dynamics simulations confirmed the stable interaction of ETV with eIF4E. Our findings not only reinforce the feasibility of targeting eIF4E in cancer but also demonstrate that repurposing FDA-approved drugs like Entecavir could offer a practical and efficient route to therapeutic intervention. This integrative approach opens new avenues for eIF4E-targeted strategies in oncology, aiming to selectively impair oncogenic translation.