POCKETSPPI

Discovering and exploiting hidden pockets at protein-protein interfaces

Coordinatore	THE UNIVERSITY OF EDINBURGH    more  Organization address address: OLD COLLEGE, SOUTH BRIDGE city: EDINBURGH postcode: EH8 9YL contact info Titolo: Ms. Nome: Angela Cognome: Noble Email: send email Telefono: +44 131 650 9024 Fax: +44 131 650 9023
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	100˙000 €
EC contributo	100˙000 €
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-2010-RG
Funding Scheme	MC-IRG
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-09-01   -   2015-08-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	THE UNIVERSITY OF EDINBURGH  Organization address address: OLD COLLEGE, SOUTH BRIDGE city: EDINBURGH postcode: EH8 9YL contact info Titolo: Ms. Nome: Angela Cognome: Noble Email: send email Telefono: +44 131 650 9024 Fax: +44 131 650 9023	UK (EDINBURGH)	coordinator	100˙000.00

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Protein-protein interactions play critical roles in normal human physiology, as well as in numerous diseases such as cancers and neurodegenerative disorders. However, identifying small molecule drugs to block protein interactions is a very difficult task. One of the major difficulties is that often the proteins involved are extremely flexible and readily change shape, which greatly complicates efforts to find small molecule ligands of matching shape. In this project, we aim to exploit protein flexibility to create new opportunities for drug discovery.

Interactions between a given pair of proteins commonly requires one or both partners to transiently form pockets that allow selective binding. Therefore, most protein interfaces likely possess many more binding pockets than those apparent in the static picture of a protein structure revealed by crystallographic experiments. We propose to identify these 'hidden' pockets using computational methods. Thus, we will develop and validate molecular simulation methodologies to detect hidden pockets at protein interfaces and assess their small molecule 'druggability' using docking calculations and binding site scoring functions. Such capacity would greatly strengthen the reliability of in silico drug design. We will perform virtual screens to find small molecule ligands binding to hidden pockets in medicinally important proteins such as FcgammaRIIA or PCNA. Finally, we will purchase or synthesize promising ligands and assay their activity against protein targets. These studies will allow us to test the utility of our computational approach in rational drug design.

The objectives of this research are part of a broader program we are currently developing and whose purpose is to provide a comprehensive set of computational/biophysical methods to allow the widespread targeting of seemingly 'undruggable' protein families with small molecules, thereby expanding the scope of modern molecular medicine.'