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 3unsubstituted 24oxazolidinedione 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 xray crystallography established that 3unsubstituted 24oxazolidinediones 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 3unsubstituted 24oxazolidinediones 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