Comparative analysis of virtual screening approaches in the search for novel EphA2 receptor antagonists

6533b834fe1ef96bd129e084

RESEARCH PRODUCT

Comparative analysis of virtual screening approaches in the search for novel EphA2 receptor antagonists

Massimiliano Tognolini Daniele Pala Donatella Callegari Alessio Lodola Alessio Lodola Silvia Rivara Matteo Incerti Laura Scalvini Marco Mor

subject

Cell signaling Databases Pharmaceutical drug design Pharmaceutical Science Computational biology Biology Crystallography X-Ray Molecular Docking Simulation Article Analytical Chemistry lcsh:QD241-441 Structure-Activity Relationship User-Computer Interface lcsh:Organic chemistry PPI inhibitors Drug Discovery shape screening Structure–activity relationship Physical and Theoretical Chemistry Receptor Protein Kinase Inhibitors Virtual screening Molecular Structure Drug discovery Receptor EphA2 EphA2 antagonist Organic Chemistry Ephrin-A1 virtual screening EPH receptor A2 C700 Combinatorial chemistry Molecular Docking Simulation UniPR129 Chemistry (miscellaneous)Docking (molecular)docking Molecular Medicine pharmacophore search

description

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.

year	journal	country	edition	language
2015-09-17

10.3390/molecules200917132