Molecular Structure Analysis Core Facility-W160, German Cancer Research Center, 69120 Heidelberg, Germany.
Biognos AB, Generatorsgatan 1, 40274 Göteborg, Sweden.
J Med Chem. 2023 Oct 26;66(20):14315-14334. doi: 10.1021/acs.jmedchem.3c01349. Epub 2023 Oct 4.
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.
Siglec-7 调节免疫细胞活性，是免疫调节的有前途的靶点。在这里，我们报告了新型唾液酸衍生物与 Siglec-7 结合的发现。基于微秒时间尺度的分子动力学 (MD) 模拟的合成和亲和力测量，补充了基于唾液酸-Siglec-7 复合物的高质量模型。我们提供了新配体的预测结合模式的详细信息，例如，碳主链的延伸导致与受体和附近的水结构的分子相互作用模式与已知的 Siglec-7 配体不同。此外，我们揭示了 GLYCAM06 和 GAFF2 力场在模拟基于唾液酸的糖模拟物时的一些缺点。我们的结果为 Siglec-7 抑制剂的合理设计开辟了新的机会。此外，我们提供了如何使用和可视化 MD 模拟来描述和研究一般的唾液酸-Siglec 复合物的策略。
