Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors
Considering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2202360 |
| _version_ | 1827123381977219072 |
|---|---|
| author | Simone Giovannuzzi Alessandro Bonardi Paola Gratteri Alessio Nocentini Claudiu T. Supuran |
| author_facet | Simone Giovannuzzi Alessandro Bonardi Paola Gratteri Alessio Nocentini Claudiu T. Supuran |
| author_sort | Simone Giovannuzzi |
| collection | DOAJ |
| description | Considering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active site among the other hCA isoforms, i.e. the Leu198/Phe198 substitution which interferes with the binding of aromatic/heterocyclic sulfonamides and other inhibitors. Thus, new aliphatic primary sulfonamides possessing long and flexible (CH2)nSO2NH2 moieties were designed to coordinate the zinc(II) ion, bypassing the bulky Phe198 residue. They incorporate 1,2,3-triazole linkers which connect the tail moieties to the sulfonamide head, enhancing thus the contacts at the active site entrance. Some of these compounds act as nanomolar and selective inhibitors of hCA III over other isoforms. Docking/molecular dynamics simulations were used to investigate ligand/target interactions for these sulfonamides which might improve our understanding of the physio-pathological roles of hCA III. |
| first_indexed | 2024-03-09T02:02:24Z |
| format | Article |
| id | doaj.art-0d1cac7dbab14fcaad0a75ab557ea796 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:24:02Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-0d1cac7dbab14fcaad0a75ab557ea7962024-09-09T17:23:18ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2202360Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitorsSimone Giovannuzzi0Alessandro Bonardi1Paola Gratteri2Alessio Nocentini3Claudiu T. Supuran4NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Firenze, ItalyNEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, ItalyNEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, ItalyNEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Firenze, ItalyNEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Firenze, ItalyConsidering the unrecognised physio-pathological role of human carbonic anhydrase III (hCA III), a structure-based drug design was set up to identify the first-in-class potent and selective inhibitors of this neglected isoform. hCA III targeting was planned considering a unique feature of its active site among the other hCA isoforms, i.e. the Leu198/Phe198 substitution which interferes with the binding of aromatic/heterocyclic sulfonamides and other inhibitors. Thus, new aliphatic primary sulfonamides possessing long and flexible (CH2)nSO2NH2 moieties were designed to coordinate the zinc(II) ion, bypassing the bulky Phe198 residue. They incorporate 1,2,3-triazole linkers which connect the tail moieties to the sulfonamide head, enhancing thus the contacts at the active site entrance. Some of these compounds act as nanomolar and selective inhibitors of hCA III over other isoforms. Docking/molecular dynamics simulations were used to investigate ligand/target interactions for these sulfonamides which might improve our understanding of the physio-pathological roles of hCA III.https://www.tandfonline.com/doi/10.1080/14756366.2023.2202360Drug designmetalloenzymeinhibitionclick chemistryhCA IIImolecular dynamics |
| spellingShingle | Simone Giovannuzzi Alessandro Bonardi Paola Gratteri Alessio Nocentini Claudiu T. Supuran Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Drug design metalloenzyme inhibition click chemistry hCA III molecular dynamics |
| title | Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors |
| title_full | Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors |
| title_fullStr | Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors |
| title_full_unstemmed | Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors |
| title_short | Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors |
| title_sort | discovery of the first in class potent and isoform selective human carbonic anhydrase iii inhibitors |
| topic | Drug design metalloenzyme inhibition click chemistry hCA III molecular dynamics |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2202360 |
| work_keys_str_mv | AT simonegiovannuzzi discoveryofthefirstinclasspotentandisoformselectivehumancarbonicanhydraseiiiinhibitors AT alessandrobonardi discoveryofthefirstinclasspotentandisoformselectivehumancarbonicanhydraseiiiinhibitors AT paolagratteri discoveryofthefirstinclasspotentandisoformselectivehumancarbonicanhydraseiiiinhibitors AT alessionocentini discoveryofthefirstinclasspotentandisoformselectivehumancarbonicanhydraseiiiinhibitors AT claudiutsupuran discoveryofthefirstinclasspotentandisoformselectivehumancarbonicanhydraseiiiinhibitors |