POCKETSPPI
Discovering and exploiting hidden pockets at protein-protein interfaces
| Coordinatore | THE UNIVERSITY OF EDINBURGH
Organization address
address: OLD COLLEGE, SOUTH BRIDGE contact info |
| 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
| # | ||||
|---|---|---|---|---|
| 1 |
THE UNIVERSITY OF EDINBURGH
Organization address
address: OLD COLLEGE, SOUTH BRIDGE contact info |
UK (EDINBURGH) | coordinator | 100˙000.00 |
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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.'