Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein–Protein Interaction Inhibitors Targeting the EphA2 Receptor

Metadynamics
(META-D) is emerging as a powerful method for the
computation of the multidimensional free-energy surface (FES) describing
the protein–ligand binding process. Herein, the FES of unbinding
of the antagonist N-(3α-hydroxy-5β-cholan-24-oyl)-l-β-homotryptophan (UniPR129) from its EphA2 receptor
was reconstructed by META-D simulations. The characterization of the
free-energy minima identified on this FES proposes a binding mode
fully consistent with previously reported and new structure–activity
relationship data. To validate this binding mode, new N-(3α-hydroxy-5β-cholan-24-oyl)-l-β-homotryptophan
derivatives were designed, synthesized, and tested for their ability
to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists,
namely compounds 21 and 22, displayed high
affinity versus the EphA2 receptor and resulted endowed with better
physicochemical and pharmacokinetic properties than the parent compound.
These findings highlight the importance of free-energy calculations
in drug design, confirming that META-D simulations can be used to
successfully design novel bioactive compounds.