RaDiTDruS: un metodo di scoring per la valutazione della druggability dei target nelle malattie rare

Rare diseases are conditions of genetic origin afflicting about 400 million people globally that are oftentimes neglected due to a variety of issues such as the minute patient pool and the wide symptomatic variability and similitude between diseases. Despite recent progresses, less than 10% of rare diseases have an approved treatment option. So, in a research landscape mostly dominated by biomedical and genetic expertise, this work first describes the “Rare Disease Target Druggability Score”, a structure-based method for assessing the druggability of protein products originated from mutated DNA. RaDiTDruS sets rules to score the availability of reliable 3D models, the extension of the known interactome, the number of mutations that reach the protein level. The final aim of the “Rare Disease Target Druggability Score” is ranking targets that are more likely to yield successful results (i.e. molecular mechanisms of pathogenicity and eventually drug candidates) upon computational study. Following the results of RaDiTDruS’s ranking, the second step of this study is its application on the top scorer protein (UBE2I) of a target list collected in the Regina Margherita Hospital of Turin. This stage of the study concentrates on the protein structure in terms of order, stability and flexibility as well as surface properties and molecular mechanisms. The results of these in-silico analyses allowed to identify the potential pathogenic mechanism that each mutation introduces in the protein.