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 CO<sub>2</sub> 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-...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/16/12619 |
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| author | Nannan Zheng Wanyun Jiang Puyu Zhang Le Ma Junzhao Chen Haiyang Zhang |
| author_facet | Nannan Zheng Wanyun Jiang Puyu Zhang Le Ma Junzhao Chen Haiyang Zhang |
| author_sort | Nannan Zheng |
| collection | DOAJ |
| description | Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO<sub>2</sub> 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 Zn<sup>2+</sup>-dependent metallo-enzyme, the influence of Zn<sup>2+</sup> 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 Zn<sup>2+</sup> ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn<sup>2+</sup>–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. |
| first_indexed | 2024-03-10T23:53:44Z |
| format | Article |
| id | doaj.art-d0db8e0aab57478f914a41261d21c058 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:53:44Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d0db8e0aab57478f914a41261d21c0582023-11-19T01:26:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161261910.3390/ijms241612619Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational StudyNannan Zheng0Wanyun Jiang1Puyu Zhang2Le Ma3Junzhao Chen4Haiyang Zhang5Department of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, ChinaHuman carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO<sub>2</sub> 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 Zn<sup>2+</sup>-dependent metallo-enzyme, the influence of Zn<sup>2+</sup> 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 Zn<sup>2+</sup> ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn<sup>2+</sup>–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.https://www.mdpi.com/1422-0067/24/16/12619receptor-ligand interactionmetallo-enzymesdrug repurposingmolecular simulation |
| spellingShingle | Nannan Zheng Wanyun Jiang Puyu Zhang Le Ma Junzhao Chen Haiyang Zhang Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study International Journal of Molecular Sciences receptor-ligand interaction metallo-enzymes drug repurposing molecular simulation |
| title | Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study |
| title_full | Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study |
| title_fullStr | Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study |
| title_full_unstemmed | Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study |
| title_short | Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study |
| title_sort | repurposing of world approved drugs for potential inhibition against human carbonic anhydrase i a computational study |
| topic | receptor-ligand interaction metallo-enzymes drug repurposing molecular simulation |
| url | https://www.mdpi.com/1422-0067/24/16/12619 |
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