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Molecules 2015, 20(9), 17132-17151; doi:10.3390/molecules200917132

Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists

1
Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy
2
Department of Applied Sciences, Northumbria University at Newcastle, Newcastle-Upon-Tyne, NE1 8ST, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Philippe Roche
Received: 3 August 2015 / Revised: 8 September 2015 / Accepted: 11 September 2015 / Published: 17 September 2015
(This article belongs to the Special Issue Small Molecules Modulation in Protein-Protein Interactions)

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. View Full-Text
Keywords: drug design; PPI inhibitors; EphA2 antagonist; UniPR129; virtual screening; shape screening; pharmacophore search; docking drug design; PPI inhibitors; EphA2 antagonist; UniPR129; virtual screening; shape screening; pharmacophore search; docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Callegari, D.; Pala, D.; Scalvini, L.; Tognolini, M.; Incerti, M.; Rivara, S.; Mor, M.; Lodola, A. Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists. Molecules 2015, 20, 17132-17151.

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