Insight to the binding mode of triazole RGD-peptidomimetics to integrin-rich cancer cells by NMR and molecular modeling

• Published in: Bioorganic & medicinal chemistry 2016-03, Vol.24 (5), p.989-994
• Main Authors: Vasile, Francesca, Menchi, Gloria, Lenci, Elena, Guarna, Antonio, Potenza, Donatella, Trabocchi, Andrea
• Format: Article
• Language: English
• Subjects: Angiogenesis; Humans; Integrin alphaVbeta3 - metabolism; Ligand–protein interaction; Magnetic Resonance Spectroscopy; Molecular docking; Molecular Docking Simulation; Oligopeptides - chemistry; Oligopeptides - metabolism; Peptidomimetics - chemistry; Peptidomimetics - metabolism; Protein Binding; Small molecule; STD-NMR; Triazoles - chemistry; Triazoles - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.01.023

[Display omitted] The binding features of a novel class of ‘click chemistry’-derived RGD mimics with integrin ligand capability were studied toward αvβ3 integrin using STD-NMR techniques on intact integrin-rich ECV340 bladder cancer cell line. STD is useful to identify which moieties of the ligand are closest to the receptor in the bound state. The NMR data were integrated with competitive binding assays to the purified αvβ3 receptor and were interpreted with the aid of docking calculations. The involvement of the triazole hydrogen atom in the interaction with the receptor was evinced for all compounds but 2, in agreement with docking studies showing a certain proximity between triazole and Tyr178. Moreover, the interaction of the hydroxylated ligands with the receptor was not as extended as in the compounds belonging to the corresponding series, with the exception of compound 4 having 2-aminobenzimidazole as the arginine bioisostere, in agreement with biological assay results showing reduced binding capability for the hydroxylated peptidomimetics.