5U0F

Identification of a New Zinc Binding Chemotype by Fragment Screening

Summary for 5U0F

• Entry DOI: 10.2210/pdb5u0f/pdb
• Related: 5TY1 5TY8 5TY9 5TYA 5U0D 5U0E 5U0G
• Descriptor: Carbonic anhydrase 2, ZINC ION, (5R)-5-[(2,4-dimethoxyphenyl)methyl]-2-sulfanylidene-1,3-thiazolidin-4-one, ... (4 entities in total)
• Functional Keywords: fragment screening, carbonic anhydrase, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29637.84

Authors

Peat, T.S.,Poulsen, S.A.,Ren, B.,Dolezal, O.,Woods, L.A.,Mujumdar, P.,Chrysanthopoulos, P.K. (deposition date: 2016-11-23, release date: 2017-08-30, Last modification date: 2023-10-04)

Primary citation

Chrysanthopoulos, P.K.,Mujumdar, P.,Woods, L.A.,Dolezal, O.,Ren, B.,Peat, T.S.,Poulsen, S.A.
Identification of a New Zinc Binding Chemotype by Fragment Screening.
J. Med. Chem., 60:7333-7349, 2017

PubMed 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.

PubMed: 28817930
DOI: 10.1021/acs.jmedchem.7b00606

Experimental method

X-RAY DIFFRACTION (1.21 Å)