Community Research and Development Information Service - CORDIS

FP7

PocketsPPI Result In Brief

Project reference: 276785
Funded under: FP7-PEOPLE
Country: United Kingdom

Hidden protein pockets — targets for therapy

Protein-protein interactions are essential to normal physiological functioning as well as pathological conditions such as cancer. Blocking these interactions seems to be an easy way to halt disease progression but many proteins readily change shape.
Hidden protein pockets — targets for therapy
Intrinsically disordered proteins (IDPs) are very common and they lack a fixed 3D structure. Greater structural flexibility allows IDPs to display a whole spectrum of states but this makes it harder to design appropriate ligands to stop interaction. However, such proteins transiently form pockets for selective binding and these pockets can be therapeutically targeted. Pocket detection and targeting is a whole new ball game in drug design.

EU funded researchers initiated the POCKETSPPI (Discovering and exploiting hidden pockets at protein-protein interfaces) project to develop new computational methodologies and validate their utility in discovering such hidden protein pockets. Their goal was to find more "druggable" alternative conformational states in IDPs such as c-Myc. C-Myc is a transcription factor that is over-expressed in most forms of cancer.

A key achievement is the development of the JEDI (just exploring druggability at protein interfaces) algorithm. This allows researchers to predict the druggability of a protein structure. Moreover, the druggability descriptor of this algorithm is fully compatible with "on the fly" molecular dynamics simulations. This is important as the researchers can now perform biased molecular dynamics simulations to steer protein conformations towards previously unknown druggable conformational states.

Simulations for c-Myc revealed the lack of stable hidden pockets suggesting that inhibitors bind to it through weak, non-specific interactions. Research outcomes were published in leading chemistry journals.

The POCKETSPPI team also worked on developing cyclophilin inhibitors for the treatment of hepatitis C, a chronic liver condition. They began with the characterisation of macrocyclic ligands and small fragments that bind to cyclophilins. Results are promising with novels fragments identified that bind weakly to different cyclophilin proteins.

Despite the end of the project, work is ongoing to further optimise the JEDI tool. Moreover, researchers have obtained funding to work on improving the binding affinity and selectivity of the cyclophilin fragments. Project outcomes have significant implications for the rational design of ligands that target IDPs such as c-Myc and cyclophilin with innumerable applications in biomedicine.

Related information

Keywords

Protein, pocket, therapy, cancer, IDP, c-Myc, cyclophilin, JEDI, molecular dynamics simulation, inhibitor, hepatitis C
Record Number: 183201 / Last updated on: 2016-08-17
Domain: Biology, Medicine