Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation
Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/21/7325 |
| _version_ | 1827765581292503040 |
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| author | Wanyun Jiang Junzhao Chen Puyu Zhang Nannan Zheng Le Ma Yongguang Zhang Haiyang Zhang |
| author_facet | Wanyun Jiang Junzhao Chen Puyu Zhang Nannan Zheng Le Ma Yongguang Zhang Haiyang Zhang |
| author_sort | Wanyun Jiang |
| collection | DOAJ |
| description | Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and CHEMBL114083 as reference molecules, here we perform a ligand-based virtual screening of world-approved drugs via 2D/3D similarity search methods, followed by the assessments of molecular docking, toxicity prediction, molecular simulation, and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) analysis. The 2D molecular fingerprinting of ECFP4 and FCFP4 and 3D molecule-shape-based USRCAT methods show good performances in selecting compounds with a strong binding behavior with ALDH2. Three compounds of Zeaxanthin (<i>q</i> = 0), Troglitazone (<i>q</i> = 0), and Sequinavir (<i>q</i> = +1 <i>e</i>) are singled out as potential inhibitors; Zeaxanthin can only be hit via USRCAT. These drugs displayed a stronger binding strength compared to the reported potent inhibitor CVT-10216. Sarizotan (<i>q</i> = +1 <i>e</i>) and Netarsudil (<i>q</i> = 0/+1 <i>e</i>) displayed a strong binding strength with ALDH2 as well, whereas they displayed a shallow penetration into the substrate-binding tunnel of ALDH2 and could not fully occupy it. This likely left a space for substrate binding, and thus they were not ideal inhibitors. The MM–PBSA results indicate that the selected negatively charged compounds from the similarity search and Vina scoring are thermodynamically unfavorable, mainly due to electrostatic repulsion with the receptor (<i>q</i> = −6 <i>e</i> for ALDH2). The electrostatic attraction with positively charged compounds, however, yielded very strong binding results with ALDH2. These findings reveal a deficiency in the modeling of electrostatic interactions (in particular, between charged moieties) in the virtual screening via the 2D/3D similarity search and molecular docking with the Vina scoring system. |
| first_indexed | 2024-03-11T11:25:36Z |
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| id | doaj.art-aef7d6d12ea548aea1ded0241bf0bb14 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T11:25:36Z |
| publishDate | 2023-10-01 |
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| series | Molecules |
| spelling | doaj.art-aef7d6d12ea548aea1ded0241bf0bb142023-11-10T15:08:37ZengMDPI AGMolecules1420-30492023-10-012821732510.3390/molecules28217325Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular SimulationWanyun Jiang0Junzhao Chen1Puyu Zhang2Nannan Zheng3Le Ma4Yongguang Zhang5Haiyang Zhang6Department of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaDepartment of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing100083, ChinaAldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and CHEMBL114083 as reference molecules, here we perform a ligand-based virtual screening of world-approved drugs via 2D/3D similarity search methods, followed by the assessments of molecular docking, toxicity prediction, molecular simulation, and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) analysis. The 2D molecular fingerprinting of ECFP4 and FCFP4 and 3D molecule-shape-based USRCAT methods show good performances in selecting compounds with a strong binding behavior with ALDH2. Three compounds of Zeaxanthin (<i>q</i> = 0), Troglitazone (<i>q</i> = 0), and Sequinavir (<i>q</i> = +1 <i>e</i>) are singled out as potential inhibitors; Zeaxanthin can only be hit via USRCAT. These drugs displayed a stronger binding strength compared to the reported potent inhibitor CVT-10216. Sarizotan (<i>q</i> = +1 <i>e</i>) and Netarsudil (<i>q</i> = 0/+1 <i>e</i>) displayed a strong binding strength with ALDH2 as well, whereas they displayed a shallow penetration into the substrate-binding tunnel of ALDH2 and could not fully occupy it. This likely left a space for substrate binding, and thus they were not ideal inhibitors. The MM–PBSA results indicate that the selected negatively charged compounds from the similarity search and Vina scoring are thermodynamically unfavorable, mainly due to electrostatic repulsion with the receptor (<i>q</i> = −6 <i>e</i> for ALDH2). The electrostatic attraction with positively charged compounds, however, yielded very strong binding results with ALDH2. These findings reveal a deficiency in the modeling of electrostatic interactions (in particular, between charged moieties) in the virtual screening via the 2D/3D similarity search and molecular docking with the Vina scoring system.https://www.mdpi.com/1420-3049/28/21/7325drug repurposingligand-based virtual screeningsubstance use disorderreceptor–ligand interactions |
| spellingShingle | Wanyun Jiang Junzhao Chen Puyu Zhang Nannan Zheng Le Ma Yongguang Zhang Haiyang Zhang Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation Molecules drug repurposing ligand-based virtual screening substance use disorder receptor–ligand interactions |
| title | Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation |
| title_full | Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation |
| title_fullStr | Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation |
| title_full_unstemmed | Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation |
| title_short | Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation |
| title_sort | repurposing drugs for inhibition against aldh2 via a 2d 3d ligand based similarity search and molecular simulation |
| topic | drug repurposing ligand-based virtual screening substance use disorder receptor–ligand interactions |
| url | https://www.mdpi.com/1420-3049/28/21/7325 |
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