6SDS

HUMAN CARBONIC ANHYDRASE II IN COMPLEX WITH A SULFONAMIDE INHIBITOR

Summary for 6SDS

• Entry DOI: 10.2210/pdb6sds/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, phenyl-(4-sulfamoylphenoxy)phosphinic acid, ... (5 entities in total)
• Functional Keywords: carbonic anhydrase ii, zinc enzyme, sulfonamide inhibitor, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29745.87

Authors

Alterio, V.,De Simone, G.,Esposito, D. (deposition date: 2019-07-29, release date: 2020-06-10, Last modification date: 2024-01-24)

Primary citation

Nocentini, A.,Alterio, V.,Bua, S.,Micheli, L.,Esposito, D.,Buonanno, M.,Bartolucci, G.,Osman, S.M.,ALOthman, Z.A.,Cirilli, R.,Pierini, M.,Monti, S.M.,Di Cesare Mannelli, L.,Gratteri, P.,Ghelardini, C.,De Simone, G.,Supuran, C.T.
Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy.
J.Med.Chem., 63:5185-5200, 2020

PubMed Abstract: Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates -. X-ray crystallography depicted the binding mode of phosphonic acid to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the ()-enantiomer, allowed to halve the dose totally relieving allodynia in mice.

PubMed: 32364386
DOI: 10.1021/acs.jmedchem.9b02135

Experimental method

X-RAY DIFFRACTION (1.26 Å)