Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics
Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-08, Vol.67 (16), p.13813-13828 |
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| container_issue | 16 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 67 |
| creator | Nemli, Dilara D. Jiang, Xiaohua Jakob, Roman P. Gloder, Laura Muñoz Schwardt, Oliver Rabbani, Said Maier, Timm Ernst, Beat Cramer, Jonathan |
| description | Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN. |
| doi_str_mv | 10.1021/acs.jmedchem.4c00623 |
| format | Article |
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Med. Chem</addtitle><description>Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. 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By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38771131</pmid><doi>10.1021/acs.jmedchem.4c00623</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-5787-2297</orcidid><orcidid>https://orcid.org/0000-0001-9869-5645</orcidid><orcidid>https://orcid.org/0000-0002-7459-1363</orcidid></addata></record> |
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| subjects | Binding Sites Cell Adhesion Molecules - chemistry Cell Adhesion Molecules - metabolism Drug Design Humans Hydrogen Bonding Lectins, C-Type - chemistry Lectins, C-Type - metabolism Ligands Mannose - chemistry Mannose - metabolism Models, Molecular Receptors, Cell Surface - chemistry Receptors, Cell Surface - metabolism Thermodynamics |
| title | Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics |
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