title: Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists.
abstract: The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS) protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. donatella.callegari@studenti.unipr.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Callegari
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. daniele.pala@nemo.unipr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. laura.scalvini@studenti.unipr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Scalvini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. massimiliano.tognolini@unipr.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. matteo.incerti@unipr.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. silvia.rivara@unipr.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. marco.mor@unipr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy. alessio.lodola@unipr.it.|Department of Applied Sciences, Northumbria University at Newcastle, Newcastle-Upon-Tyne, NE1 8ST, UK. alessio.lodola@unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D018360:Crystallography, X-Ray; D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D036382:Ephrin-A1 / Q000819:agonists* / Q000737:chemistry; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D036382:Ephrin-A1; D047428:Protein Kinase Inhibitors; D036104:Receptor, EphA2
keywords: EphA2 antagonist; PPI inhibitors; UniPR129; docking; drug design; pharmacophore search; shape screening; virtual screening