Synthesis and binding mode predictions of novel Siglec-7 ligands
Siglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis and affinity measurements are complemented by high-quality models of sialoside-Siglec-7 complexes based on molecular d...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
4 October 2023
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| In: |
Journal of medicinal chemistry
Year: 2023, Volume: 66, Issue: 20, Pages: 14315-14334 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.3c01349 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.3c01349
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| Author Notes: | Martin Frank, Elena Kuhfeldt, Jonathan Cramer, Carsten Watzl, and Horst Prescher |
| Summary: | Siglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis and affinity measurements are complemented by high-quality models of sialoside-Siglec-7 complexes based on molecular dynamics (MD) simulations on the microsecond time scale. We provide details for the predicted binding modes for the new ligands, e.g., that an extension of the carbon backbone leads to a different molecular interaction pattern with the receptor and the nearby water structure than found for known Siglec-7 ligands. Further on, we uncover some shortcomings of the GLYCAM06 and GAFF2 force fields when used for the simulation of sialoside-based glycomimetics. Our results open new opportunities for the rational design of Siglec-7 inhibitors. In addition, we provide strategies on how to use and visualize MD simulations to describe and investigate sialoside-Siglec complexes in general. |
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| Item Description: | Gesehen am 19.12.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.3c01349 |