title: Insight to the binding mode of triazole RGD-peptidomimetics to integrin-rich cancer cells by NMR and molecular modeling.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Milano, Via C. Golgi, 19, 20133 Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Vasile
authors.affiliation: Department of Chemistry 'Ugo Schiff', University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Menchi
authors.affiliation: Department of Chemistry 'Ugo Schiff', University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lenci
authors.affiliation: Department of Chemistry 'Ugo Schiff', University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
authors.affiliation: Department of Chemistry, University of Milano, Via C. Golgi, 19, 20133 Milano, Italy. Electronic address: donatella.potenza@unimi.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Potenza
authors.affiliation: Department of Chemistry 'Ugo Schiff', University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy. Electronic address: andrea.trabocchi@unifi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
mesh_terms: D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D057786:Peptidomimetics / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D057786:Peptidomimetics; D014230:Triazoles; C047981:arginyl-glycyl-aspartic acid
keywords: Angiogenesis; Ligand–protein interaction; Molecular docking; STD-NMR; Small molecule