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Beyond structure: integrated computational and experimental approach to Ensemble-Based Drug Design

Final Report Summary - EBDD (Beyond structure: integrated computational and experimental approach to Ensemble-Based Drug Design.)

The ERC starting grant EBDD has made fundamental contributions to our ability to develop therapeutics by exploiting the dynamics of protein-ligand interactions. The function of biomolecules such as proteins often depends on their ability to adopt different shapes in response to various stimuli. Drug designers often seek to develop new therapeutics by searching for man-made molecules (ligands) that may effectively and selectively recognise a given protein shape. However it is challenging to use current experimental methodologies to determine with high resolution the range of distinct shapes a protein may adopt. Thus drug designers often have to base their design on limited experimental information about the intended drug target.

Our work has led to the development and validation of a range of computer simulation methodologies to compute the different shapes a protein or a protein-ligand complex may adopt. We have further demonstrated how the computational methodologies we developed may be integrated with biophysical methods to drive the design and interpretation of experiments designed to characterise protein shapes that are otherwise invisible to conventional methodologies. This body of work on computation and experiments has already been described across more than fifteen publications, with several additional under draft and peer-review stage at the time of writing of this report. A specific highlight includes the discovery of a novel family of sub-type selective cyclophilin ligands by combination of molecular simulations with biophysical assays and biochemical structure determination. These compounds are currently being further explored as possible therapeutics for the treatment of cancers, neurodegenerative disorders and fibrotic diseases. Another highlight is the development of a novel methodology that combines molecular dynamics simulations with NMR measurements and site-directed mutagenesis experiments to characterise in atomic details shapes the enzyme cyclophilin A transiently adopts. This novel structural information will influence the course of cyclophilin drug discovery programs.

In summary, EBDD basic research activities in protein-ligand dynamics have led to the development of a computational drug discovery platform; and its validation by identification of novel bioactive small molecules. The results of this research are currently being further developed into software and tool molecules suitable for industrial drug discovery processes via collaborations with a range of software and pharmaceutical companies.