Discovery of Eriodictyol as Putative Exportin-1 Inhibitor for Non-small Cell Lung Cancer Therapy

Abstract

Exportin-1, the ubiquitous nuclear protein transporter, is widely confirmed as an active chemotherapeutic target in non-small cell lung cancer conditions, while Juglans mandshurica is a well-studied anticancer plant in some lung cancer cell lines. We intend to find a novel exportin-1 inhibitor from Juglans mandshurica with better potential, tolerability and pharmaco-dynamo-kinetic properties than the current selective inhibitors of nuclear export in non-small cell lung cancer treatment. OSIRIS DataWarrior, along with Glide standard precision docking, and other Glide modules were employed for compound properties exploration, docking simulations, free energy calculations against exportin-1; density functional theory analysis of the compounds were carried out to estimate their electronic stability, while web-based SWISSADME was employed for ADMET and synthetic accessibility evaluations. This study reveals eriodictyol as having higher binding free energy (-40 kcal/mol) than that of standard (-39.56 kcal/mol) in exportin-1 active site, better synthetic accessibility score (3.15 versus 3.29), high GI absorption, non-blood brain barrier permeant, lacks Brenk and PAINS alert, obeying Lipinski’s, Ghose’s, Veber’s, Egan’s, and Muegge’s rule of drug-likeness and lead-likeness as well as non-cytotoxic to HepG2 cells. We therefore found eriodictyol as a lead-like, non-toxic exportin-1 inhibitor with good predictive stability and pharmacokinetic potential and thus provided data for further validation of eriodictyol as a candidate exportin-1 inhibitor in both preclinical and clinical studies involving lung cancer therapy.