jm6b01642_si_002.pdb (228.05 kB)

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

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posted on 22.12.2016 by Matteo Incerti, Simonetta Russo, Donatella Callegari, Daniele Pala, Carmine Giorgio, Ilaria Zanotti, Elisabetta Barocelli, Paola Vicini, Federica Vacondio, Silvia Rivara, Riccardo Castelli, Massimiliano Tognolini, Alessio Lodola
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.