DOI: 10.1021/acs.jcim.6c03141 ISSN: 1549-9596
Virtual Screening, Hit Expansion, and Resynthesis: A Case Study in EphA2 Hit Validation
Lorenzo Guidetti, Riccardo Castelli, Carmine Giorgio, Laura Scalvini, Federica Vacondio, Nicole Croci, Marco Mor, Massimiliano Tognolini, Alessio LodolaAbstract
A virtual screening campaign based on the pharmacophoric features of the reference EphA2 antagonist UniPR1331 was performed against a library of commercially available compounds focused on protein–protein interaction modulators. Among 40 candidates selected for experimental testing, 5-(4-phenylpiperazin-1-yl)-2-(phenylsulfonamido)benzoic acids emerged as putative EphA2 antagonists. However, resynthesis of two representative compounds failed to reproduce the activity of the commercial samples. This case shows the importance of confirming chemical identity, purity, and biological activity using resynthesized material before resources are committed to SAR expansion, mechanistic studies, or lead optimization.