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.

Probing the Binding Site of Abl Tyrosine Kinase Using in Situ Click Chemistry / C. Peruzzotti, S. Borrelli, M. Ventura, R. Pantano, G. Fumagalli, M. Christodoulou, D. Monticelli, M. Luzzani, A.L. Fallacara, C. Tintori, M. Botta, D. Passarella. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 4:2(2013 Feb), pp. 274-277. [10.1021/ml300394w]

Probing the Binding Site of Abl Tyrosine Kinase Using in Situ Click Chemistry

S. Borrelli;M. Christodoulou;D. Passarella
2013

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.
ligand-binding site ; Abl tyrosine kinase ; click chemistry ; drug design synthesis
Settore CHIM/06 - Chimica Organica
feb-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/217262
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