„Transient protein states in designing small-molecule inhibitors of protein-protein interactions”
Project supported by the National Science Centre, Poland under the „SYMFONIA 2” programme
Total cost: 6 496 000,00 PLN
Centre Contribution: 1 844 400,00 PLN
Principal Investigator: prof. dr hab. Jacek Otlewski
- Uniwersytet Jagielloński – Consortium Leader
- Wrocławskie Centrum Badań EIT+ Sp. z o.o.
The objective of our proposal is to show that small organic molecules which stabilize selected, transient conformational states of proteins can be rationally designed and used as novel chemical probes in cell biology and pharmacology. We concentrate on small-molecule compounds for new, emerging, cancer-related protein-protein interactions (PPIs). Small-molecule probes developed by us should decipher the mechanism of the involvement of these PPIs in tumorigenesis. Despite the availability of human genome information and growing number of structural and functional data, it is still not possible to rationally design novel chemical probes. We propose to solve this problem by enabling the development of new small-molecule candidates that are not limited to features mimicking native interactions but are designed to take advantage of the protein interface natural flexibility. This approach is a fundamental paradigm shift over traditional small-molecule design. To our knowledge it was never applied rationally to PPI yet. The major obstacle being until now: poor understanding of the interfaceformation dynamics and focus on the static, X-ray crystallography derived models of interactions.