Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I : A Computational Study
Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO2 and are acknowledged as promising targets for the treatment of various diseases. Using molecular docking and molecular dynamics simulation approaches, we hit three compounds of methyl 4-chloranyl-2-(phenylsulfonyl)-5-sulfamoyl-benzoate (84Z for short), cyclothiazide, and 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzenesulfonamide (3UG for short) from the existing hCA I inhibitors and word-approved drugs. As a Zn2+-dependent metallo-enzyme, the influence of Zn2+ ion models on the stability of metal-binding sites during MD simulations was addressed as well. MM-PBSA analysis predicted a strong binding affinity of -18, -16, and -14 kcal/mol, respectively, for these compounds, and identified key protein residues for binding. The sulfonamide moiety bound to the Zn2+ ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn2+-sulfonamide distance, although the relative binding strength was reproduced with good accuracy. The selected compounds displayed potent inhibition against other hCA isoforms of II, XIII, and XIV. This work is valuable for molecular modeling of hCAs and further design of potent inhibitors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
International journal of molecular sciences - 24(2023), 16 vom: 09. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zheng, Nannan [VerfasserIn] |
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| Links: |
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| Themen: |
21240MF57M |
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| Anmerkungen: |
Date Completed 28.08.2023 Date Revised 29.08.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms241612619 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361269811 |
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| 100 | 1 | |a Zheng, Nannan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I |b A Computational Study |
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| 500 | |a Date Completed 28.08.2023 | ||
| 500 | |a Date Revised 29.08.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO2 and are acknowledged as promising targets for the treatment of various diseases. Using molecular docking and molecular dynamics simulation approaches, we hit three compounds of methyl 4-chloranyl-2-(phenylsulfonyl)-5-sulfamoyl-benzoate (84Z for short), cyclothiazide, and 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzenesulfonamide (3UG for short) from the existing hCA I inhibitors and word-approved drugs. As a Zn2+-dependent metallo-enzyme, the influence of Zn2+ ion models on the stability of metal-binding sites during MD simulations was addressed as well. MM-PBSA analysis predicted a strong binding affinity of -18, -16, and -14 kcal/mol, respectively, for these compounds, and identified key protein residues for binding. The sulfonamide moiety bound to the Zn2+ ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn2+-sulfonamide distance, although the relative binding strength was reproduced with good accuracy. The selected compounds displayed potent inhibition against other hCA isoforms of II, XIII, and XIV. This work is valuable for molecular modeling of hCAs and further design of potent inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a drug repurposing | |
| 650 | 4 | |a metallo-enzymes | |
| 650 | 4 | |a molecular simulation | |
| 650 | 4 | |a receptor-ligand interaction | |
| 650 | 7 | |a Carbonic Anhydrase I |2 NLM | |
| 650 | 7 | |a EC 4.2.1.- |2 NLM | |
| 650 | 7 | |a Carbonic Anhydrases |2 NLM | |
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| 650 | 7 | |a Sulfanilamide |2 NLM | |
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| 650 | 7 | |a Sulfonamides |2 NLM | |
| 700 | 1 | |a Jiang, Wanyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Puyu |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Le |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Junzhao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Haiyang |e verfasserin |4 aut | |
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