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Thermodynamic basis of the inhibition of protein-protein interactions: design principles for the next generation of medicines

Final Report Summary - PPIDESIGN (Thermodynamic basis of the inhibition of protein-protein interactions: design principles for the next generation of medicines)

The main objective of this research were to discover novel inhibitors of protein-protein interactions that are of pharmaceutical relevance, with an initial focus on the interaction between the protein p53 and the proteins MDM2 and MDM4. To achieve this goal, state of the art computer-aided drug design methodologies were used in the Jorgensen lab at Yale University. The best in silico designs were synthesized by coworkers and the biological activity of these compounds evaluated with in vitro tests. Further structural/biophysical studies of the most potent MDM2/4 inhibitors were planned during the return phase in the Walkinshaw lab at the University of Edinburgh.

Throughout the project, the fellow has received extensive training in drug design, with a strong focus on computational methods. The fellow has used several computational methods to discover new peptidomimetic inhibitors of p53/MDM2 and p53/MDM4 which has led to a number of publications in the scientific literature. The fellow has also developed a novel computational method, named JAWS, to enhance the effectiveness of in silico drug design. The fellow was awarded the 2009 Emerging Computational Technology Prize by the American Chemical Society for his work on the development of JAWS. The method has been implemented in the widely used software MCPRO, facilitating widespread dissemination of the work of the fellow. The fellow has also applied his expertise in computer-aided drug design to related projects in collaboration with different chemical biology labs, which have led to the discovery of new small molecule modulators of protein-protein interactions. These findings have been published in the scientific literature and have attracted several highlights by popular scientific magazines (For instance, Chemical & Engineering News, Nature Chemistry, Nature Chemical Biology). The fellow has presented his work at international conferences, such as the bi-annual American Chemical Society meetings, or MGMS conferences, and has authored review articles summarizing the state-of-the art of his field of research. The research activities of the fellow have created links between the University of Edinburgh and Yale University and future projects involving researchers between the two institutions are currently in development. The fellow has also been actively involved in dissemination of his research, through the organization of specialist workshops in partnership with the UK academic organization CCPB.

Overall the research activities of the fellow have contributed to enhance the profile of in silico methods in drug design and led to the identification of new small molecule ligands of protein-protein interactions, potentially of pharmaceutical relevance. The research activities of the fellow have been beneficial to the large community of academic and industrial scientists pursuing the discovery of novel medicines. The research activities of the fellow have therefore indirectly contributed to enhancing the health and quality of life of the civil society.