Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?
The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties all...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/12/1837 |
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| author | Anna Sandner Khang Ngo Christoph P. Sager Frithjof Scheer Michael Daude Wibke E. Diederich Andreas Heine Gerhard Klebe |
| author_facet | Anna Sandner Khang Ngo Christoph P. Sager Frithjof Scheer Michael Daude Wibke E. Diederich Andreas Heine Gerhard Klebe |
| author_sort | Anna Sandner |
| collection | DOAJ |
| description | The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values. |
| first_indexed | 2024-03-10T04:33:10Z |
| format | Article |
| id | doaj.art-d281860ce9d74c0db718c7b1b1b9ce96 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T04:33:10Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-d281860ce9d74c0db718c7b1b1b9ce962023-11-23T03:59:56ZengMDPI AGBiomolecules2218-273X2021-12-011112183710.3390/biom11121837Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?Anna Sandner0Khang Ngo1Christoph P. Sager2Frithjof Scheer3Michael Daude4Wibke E. Diederich5Andreas Heine6Gerhard Klebe7Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, GermanyInstitut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, GermanyInstitut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, GermanyInstitut für Pharmazeutische Chemie, Zentrum für Tumor und Immunbiologie, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35032 Marburg, GermanyZentrum für Tumor und Immunbiologie, Core Facility Medicinal Chemistry, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, GermanyInstitut für Pharmazeutische Chemie, Zentrum für Tumor und Immunbiologie, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35032 Marburg, GermanyInstitut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, GermanyInstitut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, GermanyThe transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values.https://www.mdpi.com/2218-273X/11/12/1837diabetesaldose reductase (ALR-2)binding modeprotein-ligand interactionstructure-based drug designelectronic surface potential area (ESP) |
| spellingShingle | Anna Sandner Khang Ngo Christoph P. Sager Frithjof Scheer Michael Daude Wibke E. Diederich Andreas Heine Gerhard Klebe Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? Biomolecules diabetes aldose reductase (ALR-2) binding mode protein-ligand interaction structure-based drug design electronic surface potential area (ESP) |
| title | Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? |
| title_full | Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? |
| title_fullStr | Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? |
| title_full_unstemmed | Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? |
| title_short | Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase? |
| title_sort | which properties allow ligands to open and bind to the transient binding pocket of human aldose reductase |
| topic | diabetes aldose reductase (ALR-2) binding mode protein-ligand interaction structure-based drug design electronic surface potential area (ESP) |
| url | https://www.mdpi.com/2218-273X/11/12/1837 |
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