Throughout the last years there has been a considerable number of drugs that were discovered thanks to computer aided drug design (CADD) techniques. The use of 3D information such as protein structures obtained by X-Ray crystallography or NMR has made possible to identify the structural binding site and design molecules that have the ability to specifically target a certain protein. This approach is able to save a lot of time and money as the lead search is more accurate: less compounds need to be synthesized and tested. Although a great number of proteins could have been targeted with this new approach there are still several proteins that have been impossible to target and are considered as “undruggable”. This is because no lead compound can make it to the market due to lack of activity, high toxicity and/or the inability to detect a potential binding site that prevents the design of a suitable ligand. Now there is the presumption that the druggable human proteome may be larger than previously expected. Structures may present multiple binding sites (allosteric and/or cryptic) that have not been able to target by the means of conventional CADD techniques. Approaches like Cosolvent Molecular Dynamics have proven to be useful in the discovery of new binding sites. In this scope we’re developing a software tool that identifies potential hotspots such as allosteric sites from difficult to target proteins. CAT analyzes the behaviour of the chosen cosolvent fragments and the protein residues movements during the simulation in order to find cryptic and transient binding sites.

Cosolvent dynamics: A tool for expanding the druggable human proteome

2019 Spring National Meeting

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