Exploiting Free-Energy Minima to Design Novel EphA2 Protein-Protein Antagonists: From Simulation to Experiment and Return

The free‐energy surface (FES) of protein–ligand binding contains information useful for drug design. Here we show how to exploit a free‐energy minimum of a protein‐ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency. The free‐energy...

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Bibliographic Details
Published in:Chemistry : a European journal 2016-06, Vol.22 (24), p.8048-8052
Main Authors: Russo, Simonetta, Callegari, Donatella, Incerti, Matteo, Pala, Daniele, Giorgio, Carmine, Brunetti, Jlenia, Bracci, Luisa, Vicini, Paola, Barocelli, Elisabetta, Capoferri, Luigi, Rivara, Silvia, Tognolini, Massimiliano, Mor, Marco, Lodola, Alessio
Format: Article
Language:English
Subjects:
Binding
Binding Sites
Chemistry
computational chemistry
Design improvements
Drug Design
Drugs
Humans
Kinetics
Ligands
metadynamics
Minima
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Proteins
Receptor, EphA2 - antagonists & inhibitors
Receptor, EphA2 - metabolism
Simulation
steroids
Surface Plasmon Resonance
Thermodynamics
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Summary:The free‐energy surface (FES) of protein–ligand binding contains information useful for drug design. Here we show how to exploit a free‐energy minimum of a protein‐ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency. The free‐energy surface (FES) of protein–ligand binding contains information useful for drug design. A free‐energy minimum of a protein–ligand complex identified by metadynamics simulations can be exploited to design a new EphA2 antagonist with improved inhibitory potency.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201600993