6SDT

HUMAN CARBONIC ANHYDRASE VII IN COMPLEX WITH A SULFONAMIDE INHIBITOR

6SDT の概要

• エントリーDOI: 10.2210/pdb6sdt/pdb
• 分子名称: Carbonic anhydrase 7, ZINC ION, phenyl-(4-sulfamoylphenoxy)phosphinic acid, ... (4 entities in total)
• 機能のキーワード: carbonic anhydrase vii, zinc enzyme, inhibitor, sulfonamide, lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31304.37

構造登録者

Alterio, V.,De Simone, G.,Esposito, D. (登録日: 2019-07-29, 公開日: 2020-06-10, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.94 Å)