Molecular Dynamics Simulations Identify Tractable Lead-like Phenyl-Piperazine Scaffolds as eIF4A1 ATP-competitive Inhibitors

eIF4A1 is an ATP-dependent
RNA helicase whose overexpression and
activity have been tightly linked to oncogenesis in a number of malignancies.
An understanding of the complex kinetics and conformational changes
of this translational enzyme is necessary to map out all targetable
binding sites and develop novel, chemically tractable inhibitors.
We herein present a comprehensive quantitative analysis of eIF4A1
conformational changes using protein–ligand docking, homology
modeling, and extended molecular dynamics simulations. Through this,
we report the discovery of a novel, biochemically active phenyl-piperazine
pharmacophore, which is predicted to target the ATP-binding site and
may serve as the starting point for medicinal chemistry optimization
efforts. This is the first such report of an ATP-competitive inhibitor
for eiF4A1, which is predicted to bind in the nucleotide cleft. Our
novel interdisciplinary pipeline serves as a framework for future
drug discovery efforts for targeting eiF4A1 and other proteins with
complex kinetics.