TY  - JOUR
AU  - Frank, Martin
AU  - Kuhfeldt, Elena
AU  - Cramer, Jonathan
AU  - Watzl, Carsten
AU  - Prescher, Horst
TI  - Synthesis and Binding Mode Predictions of Novel Siglec-7 Ligands.
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 20
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2023-02010
SP  - 14315-14334
PY  - 2023
N1  - #EA:W160# / 2023 Oct 26;66(20):14315-14334
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37793071
DO  - DOI:10.1021/acs.jmedchem.3c01349
UR  - https://inrepo02.dkfz.de/record/284421
ER  -