5WLT

Carbonic Anhydrase IX-mimic in complex with aryloxy-2-hydroxypropylammine sulfonamide

5WLT の概要

• エントリーDOI: 10.2210/pdb5wlt/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 4-{(2S)-2-hydroxy-3-[(propan-2-yl)amino]propoxy}benzene-1-sulfonamide, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase, beta adrenergic receptor, sulfonamide, aryloxy-2-hydroxypropylammine, lyase, lyase-inhibitor complex, lyase/inhibitor
• 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: 30243.60

構造登録者

Lomelino, C.L.,Andring, J.T.,McKenna, R. (登録日: 2017-07-27, 公開日: 2018-08-01, 最終更新日: 2023-10-04)

主引用文献

Nocentini, A.,Ceruso, M.,Bua, S.,Lomelino, C.L.,Andring, J.T.,McKenna, R.,Lanzi, C.,Sgambellone, S.,Pecori, R.,Matucci, R.,Filippi, L.,Gratteri, P.,Carta, F.,Masini, E.,Selleri, S.,Supuran, C.T.
Discovery of beta-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy.
J. Med. Chem., 61:5380-5394, 2018

PubMed Abstract: The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β- and β-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucoma therapy with an innovative mechanism of action.

PubMed: 29851481
DOI: 10.1021/acs.jmedchem.8b00625

実験手法

X-RAY DIFFRACTION (1.57 Å)