title: Probing the binding site of abl tyrosine kinase using in situ click chemistry.
abstract: Modern combinatorial chemistry is used to discover compounds with desired function by an alternative strategy, in which the biological target is directly involved in the choice of ligands assembled from a pool of smaller fragments. Herein, we present the first experimental result where the use of in situ click chemistry has been successfully applied to probe the ligand-binding site of Abl and the ability of this enzyme to form its inhibitor. Docking studies show that Abl is able to allow the in situ click chemistry between specific azide and alkyne fragments by binding to Abl-active sites. This report allows medicinal chemists to use protein-directed in situ click chemistry for exploring the conformational space of a ligand-binding pocket and the ability of the protein to guide its inhibitor. This approach can be a novel, valuable tool to guide drug design synthesis in the field of tyrosine kinases.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peruzzotti
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: Borrelli
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Ventura
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pantano
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Fumagalli
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Christodoulou
authors.affiliation: Dipartimento di Scienze Alta Tecnologia, Università degli Studi dell'Insubria , Via Valleggio 11, 22100 Como, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Monticelli
authors.affiliation: LINNEA SA , Via Cantonale, 6595 Riazzino, Switzerland.
authors.forename: Marcello
authors.initials: M
authors.lastname: Luzzani
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena , Via Alcide de Gasperi 2, I-53100, Siena, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena , Via Alcide de Gasperi 2, I-53100, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena , Via Alcide de Gasperi 2, I-53100, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Passarella
keywords: Abl tyrosine kinase; click chemistry; drug design synthesis; ligand-binding site