small hydrophobic pocket without strong hydrogen bond interactions with P2. Therefore, an isobutyl group was kept at the P2 site. The S3 subsite is completely exposed to the solvent and only three interactions between the peptide backbone atoms of Lys3 of the substrate and the protein were observed. In addition, the lack of strong hydrogen bond interactions in the S4 sub-site supports the strategy of reducing the size of the inhibitor. Small moieties at position further than P3 were introduced with the aim of improving synthetic accessibility. Also, previous studies suggest that P3 can tolerate substituents of different shape and size, which motivated keeping the same full recognition part and changing only the warhead. This strategy allows deciphering of the effect of the warhead in the inhibition process.