Metalloenzymes are important target class for the development of chemotherapeutics and include clinically approved compounds such as captopril (ACE inhibitor, hypertension), vorinostat (HDAC inhibitor, cancer), raltegravir (Integrase inhibitor, HIV), and others (see Dalton Trans., 2011 , 40,3445-3454).  In order to advance the discovery of metalloprotein inhibitors, our group has advanced a fragment-based approach to inhibitor design.  In an attempt to better understand the binding of chelating fragments to a metalloprotein active site, we have explored the structural biology of such compounds bound to human carbonic anhydrase II (hCAII).  The binding of molecular fragments to the active site of hCAII show a substantial degree of variability and are not always successfully recapitulated by inorganic model complexes.  The findings highlight the influence of the protein active site on the of an inhibitor to the metal ion in that active site.  We are using these findings to aid in structure-based drug design and to augment computational studies on metalloprotein inhibitors.

Structural studies of metalloprotein inhibitor fragments

245th National Meeting (2013)

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