5WLT
Carbonic Anhydrase IX-mimic in complex with aryloxy-2-hydroxypropylammine sulfonamide
Summary for 5WLT
| Entry DOI | 10.2210/pdb5wlt/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, 4-{(2S)-2-hydroxy-3-[(propan-2-yl)amino]propoxy}benzene-1-sulfonamide, ... (5 entities in total) |
| Functional Keywords | carbonic anhydrase, beta adrenergic receptor, sulfonamide, aryloxy-2-hydroxypropylammine, lyase, lyase-inhibitor complex, lyase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 30243.60 |
| Authors | Lomelino, C.L.,Andring, J.T.,McKenna, R. (deposition date: 2017-07-27, release date: 2018-08-01, Last modification date: 2023-10-04) |
| Primary citation | 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 Cited by 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: 29851481DOI: 10.1021/acs.jmedchem.8b00625 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.57 Å) |
Structure validation
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