We present here a novel in silico approach to classify proteases in their peptide substrate space. Intuitively, one would expect that proteases from the same family, based on the traditional classification (aspartic, cysteine, serine and metallo), would be similar in the substrate space. However, our approach reveals that proteases from different families could also have substrates that differ at the cleavage site but are similar away from it. Caspase-3 (cysteine protease) and granzyme B (serine protease) are examples of cross-family neighbors identified by this method and supported by the presence of compounds that inhibit both. In addition, a strategy to assess whether peptide substrate similarity between unrelated proteases could reliably translate into small-molecule or drug like inhibitor similarity was tested on two other cross-family neighbors with no known shared inhibitors. The results indicate that this approach could be prospectively applied to lead discovery for a novel protease target.

Novel classification of proteases in the peptide substrate space reveals cross-family substrate similarities with applications to lead discovery

240th National Meeting (2010)

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