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Thermodynamic basis of the inhibition of protein-protein interactions: design principles for the next generation of medicines (PPIdesign)
Start date: 01 Mar 2009, End date: 31 Dec 2010 PROJECT  FINISHED 

Many biological processes are orchestrated by complex networks of protein-protein interactions and several diseases can be linked to deregulations of these convoluted networks. In spite of their central importance in diseases, very few existing drugs act by disrupting abnormal protein-protein interactions. The discovery of small molecule able to disrupt critical protein-protein interactions has long been considered a very difficult task. Yet, recent successes suggest that this endeavor is feasible but clear strategies to tackle such class of targets have not yet emerged. Among the many medically important protein-protein interactions, the binding of the oncogene MDM2 to the tumor suppressor p53 has attracted intense interest due to its central importance in cancer biology and this system has emerged as a testing ground for design strategies to target effectively protein-protein interactions. In this project, computer simulations and biophysical experiments will be conducted to discover, optimize and characterize inhibitors of the p53/MDM2 as well as the highly similar p53/MDM4 interactions. The effectiveness of the computer aided drug design methodologies will be assessed against this class of target and novel design concepts at the forefront of chemical biology will be applied to develop scaffolds able to disrupt these interactions. Key collaborations will allow the designed inhibitors to be synthesized and tested for biological activity. Thermodynamic studies will also be conducted to characterize the binding properties of successful design and critically assess the predictive power of the computational techniques. The overarching goal of this research will be to not only design potent inhibitors, potentially extraordinarily useful as anti cancer agents, but also to delineate design principles to effectively target protein-protein interactions, thereby potentially unlocking a large fraction of the proteome for future therapeutic intervention
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