Identification of a New Zinc Binding Chemotype by Fragment Screening

The discovery of a new zinc binding
chemotype from screening a
nonbiased fragment library is reported. Using the orthogonal fragment
screening methods of native state mass spectrometry and surface plasmon
resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found
to have low micromolar binding affinity to the zinc metalloenzyme
carbonic anhydrase II (CA II). This affinity approached that of fragment
sized primary benzenesulfonamides, the classical zinc binding group
found in most CA II inhibitors. Protein X-ray crystallography established
that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction
of the acidic ring nitrogen with the CA II active site zinc, as well
as two hydrogen bonds between the oxazolidinedione ring oxygen and
the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones
appear to be a viable starting point for the development of an alternative
class of CA inhibitor, wherein the medicinal chemistry pedigree of
primary sulfonamides has dominated for several decades.