KIBINDING

Improving the selectivity of kinase inhibitors: Characterizing binding mechanisms of inhibitors targeting inactive states and allosteric sites

Coordinatore	UNIVERSITY COLLEGE LONDON    more  Organization address address: GOWER STREET city: LONDON postcode: WC1E 6BT contact info Titolo: Mr. Nome: Giles Cognome: Machell Email: send email Telefono: +44 20 3108 3020 Fax: +44 20 7813 2849
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	168˙896 €
EC contributo	168˙896 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2011-IEF
Funding Scheme	MC-IEF
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-03-01   -   2015-02-28

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITY COLLEGE LONDON  Organization address address: GOWER STREET city: LONDON postcode: WC1E 6BT contact info Titolo: Mr. Nome: Giles Cognome: Machell Email: send email Telefono: +44 20 3108 3020 Fax: +44 20 7813 2849	UK (LONDON)	coordinator	168˙896.40
2	FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III  Organization address address: CALLE MELCHOR FERNANDEZ ALMAGRO 3 city: MADRID postcode: 28029 contact info Titolo: Dr. Nome: Dolores Cognome: Liebanes Email: send email Telefono: +34 917328000	ES (MADRID)	participant	0.00

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 Obiettivo del progetto (Objective)

'Kinase proteins are key to signaling in eukaryotic cells, so it is not surprising that their dysfunction has been implicated in human diseases such as cancer and inflammatory disorders. As a result, kinases have become important targets for drug discovery. The majority of kinase inhibitors bind to the ATP-binding site, which is highly conserved among the different kinases. In order to increase inhibitor selectivity toward a desired target kinase, the focus has turned to developing inhibitors which bind to inactive conformations or allosteric sites. The techniques frequently used to study inhibitor binding such as X-ray crystallography and docking are limited because they only sample a single structure. In reality, a protein is characterized by an ensemble of structures. Free energy calculations can sample many different conformations and provide a clear picture of the mechanisms of inhibitor binding. Since straightforward molecular dynamics simulations suffer from a time scale problem we use a novel computational technique, metadynamics, to enhance sampling. Using metadynamics calculations we propose to investigate the binding mechanisms of inhibitors which target the inactive conformation and allosteric sites. We focus on two proteins which are targets for cancer therapy: p38 mitogen-activated protein kinase and Abl.'