A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced‐fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell‐binding sites, NMR studies indicate greater affinity for the cell‐binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell‐binding site with the predicted protein–ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity.

中文翻译：

---

异核核磁共振波谱，计算机和体内研究揭示了在人类血管生成素细胞结合位点的新作用的证据

核糖核酸酶A超家族的成员，人血管生成素（hAng）是有效的血管生成因子。核磁共振波谱法与诱导拟合对接相结合，揭示了一系列抗血管生成呋喃糖基嘧啶核苷中最抗血管生成化合物的双重结合模式，这些化合物在体内强烈抑制hAng的血管生成活性。虽然建模表明了抑制剂在活性位点和细胞结合位点同时结合的潜力，但NMR研究表明，对细胞结合位点的亲和力大于对活性位点的亲和力。此外，在100 ns的分子动力学模拟证实了在细胞结合位点的结合具有预测的蛋白质-配体相互作用的稳定性，与NMR数据非常吻合。