Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase
Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/24/8773 |
| _version_ | 1797456079393652736 |
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| author | Boqian Zhou Yongguang Zhang Wanyun Jiang Haiyang Zhang |
| author_facet | Boqian Zhou Yongguang Zhang Wanyun Jiang Haiyang Zhang |
| author_sort | Boqian Zhou |
| collection | DOAJ |
| description | Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge <i>q</i> = +1 <i>e</i>) and olaparib (<i>q</i> = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor (<i>q</i> = −6 <i>e</i> for ALDH2 plus the cofactor NAD<sup>+</sup>). This revealed a deficiency of the Vina scoring in dealing with strong charge–charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2. |
| first_indexed | 2024-03-09T16:03:15Z |
| format | Article |
| id | doaj.art-687a42be329e45c49192fc616cba1328 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T16:03:15Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-687a42be329e45c49192fc616cba13282023-11-24T16:57:12ZengMDPI AGMolecules1420-30492022-12-012724877310.3390/molecules27248773Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde DehydrogenaseBoqian Zhou0Yongguang Zhang1Wanyun Jiang2Haiyang Zhang3Department 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, ChinaMitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge <i>q</i> = +1 <i>e</i>) and olaparib (<i>q</i> = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor (<i>q</i> = −6 <i>e</i> for ALDH2 plus the cofactor NAD<sup>+</sup>). This revealed a deficiency of the Vina scoring in dealing with strong charge–charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2.https://www.mdpi.com/1420-3049/27/24/8773virtual screeningdrug repurposingmolecular dynamics simulationalcohol addiction |
| spellingShingle | Boqian Zhou Yongguang Zhang Wanyun Jiang Haiyang Zhang Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase Molecules virtual screening drug repurposing molecular dynamics simulation alcohol addiction |
| title | Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase |
| title_full | Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase |
| title_fullStr | Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase |
| title_full_unstemmed | Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase |
| title_short | Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase |
| title_sort | virtual screening of fda approved drugs for enhanced binding with mitochondrial aldehyde dehydrogenase |
| topic | virtual screening drug repurposing molecular dynamics simulation alcohol addiction |
| url | https://www.mdpi.com/1420-3049/27/24/8773 |
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