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Identification of a New Zinc Binding Chemotype by Fragment Screening.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Chrysanthopoulos PK,Mujumdar P,Woods LA,Dolezal O,Ren B,Peat TS,Poulsen SA

doi

10.1021/acs.jmedchem.7b00606

subject

Has Abstract

pub_date

2017-09-14 00:00:00

pages

7333-7349

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

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