4Z0L

The murine cyclooxygenase-2 complexed with a nido-dicarbaborate-containing indomethacin derivative

Summary for 4Z0L

• Entry DOI: 10.2210/pdb4z0l/pdb
• Descriptor: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING FE, ... (8 entities in total)
• Functional Keywords: cyclooxygenase, indomethacin, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 4
• Total formula weight: 279778.59

Authors

Xu, S.,Neumann, W.,Banerjee, S.,Hey-Hawkins, E.,Marnett, L.J. (deposition date: 2015-03-26, release date: 2015-06-10, Last modification date: 2024-11-13)

Primary citation

Neumann, W.,Xu, S.,Sarosi, M.B.,Scholz, M.S.,Crews, B.C.,Ghebreselasie, K.,Banerjee, S.,Marnett, L.J.,Hey-Hawkins, E.
nido-Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase-2.
Chemmedchem, 11:175-178, 2016

PubMed Abstract: Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue, but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore that exhibits properties which are also highly beneficial for its introduction into other inhibitor classes.

PubMed: 26088701
DOI: 10.1002/cmdc.201500199

Experimental method

X-RAY DIFFRACTION (2.29 Å)