6B4D

Crystal structure of human carbonic anhydrase II in complex with a heteroaryl-pyrazole carboxylic acid derivative.

Replaces:  5CJL

Summary for 6B4D

• Entry DOI: 10.2210/pdb6b4d/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: carbonic anhydrase, inhibitor, carboxylic acid, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29515.71

Authors

Lomelino, C.L.,Mahon, B.P.,McKenna, R. (deposition date: 2017-09-26, release date: 2018-02-07, Last modification date: 2023-10-04)

Primary citation

Cadoni, R.,Pala, N.,Lomelino, C.,Mahon, B.P.,McKenna, R.,Dallocchio, R.,Dessi, A.,Carcelli, M.,Rogolino, D.,Sanna, V.,Rassu, M.,Iaccarino, C.,Vullo, D.,Supuran, C.T.,Sechi, M.
Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors.
ACS Med Chem Lett, 8:941-946, 2017

PubMed Abstract: We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, with = 0.21 μM toward CA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.

PubMed: 28947941
DOI: 10.1021/acsmedchemlett.7b00229

Experimental method

X-RAY DIFFRACTION (1.196 Å)