title: Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein-Protein Interaction Inhibitors Targeting the EphA2 Receptor.
abstract: 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.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Donatella
authors.identifier: 0000-0002-2574-3826
authors.initials: D
authors.lastname: Callegari
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Daniele
authors.identifier: 0000-0001-6160-6127
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanotti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vicini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Silvia
authors.identifier: 0000-0001-8058-4250
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Massimiliano
authors.identifier: 0000-0002-4715-0407
authors.initials: M
authors.lastname: Tognolini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.|Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University , Newcastle upon Tyne NE1 8ST, United Kingdom.
authors.forename: Alessio
authors.identifier: 0000-0002-8675-1002
authors.initials: A
authors.lastname: Lodola
mesh_terms: D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D004355:Drug Stability; D008024:Ligands; D008095:Lithocholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D008024:Ligands; C000600256:UniPR129; D008095:Lithocholic Acid; D014364:Tryptophan; D036104:Receptor, EphA2