Cathepsin structural biology

Kick EK, Roe DC, Skillman AG, Liu G, Ewing TJA, Sun Y, Kuntz ID, Ellman JA, Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of Cathepsin D, Chemistry and Biology, 4 297-307, 1997. 

Compound 1 had very low structural similarity to known cathepsin inhibitors. Its maximum MACCS Tc value to reference set compounds was only 0.53. The corresponding values for compounds 2 and 3 were 0.79 and 0.80, respectively, which also indicate only limited structural similarity, below the level at which similarity in biological activity is typically expected [22]. Importantly, compound 1 contains no nitrile group and is the first cathepsin inhibitor identified lacking an electrophilic group that covalently (yet reversibly) modifies the enzyme. Hence, it is expected to act by a different noncovalent mechanism, which makes it attractive for further exploration. 

Biology, 4, 297 (1997). Structure-Based Design and Combinatorial Ghemistry Yield Low Nanomolar Inhibitors of Cathepsin D. 

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