Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2020 Jan 1;28(1):115183. doi: 10.1016/j.bmc.2019.115183. Epub 2019 Nov 11.
Multifaceted roles of vascular endothelial growth factor (VEGF)-neuropilin-1 (NRP1) interaction have been implicated in cancer, but reports on small-molecule inhibitors of VEGF-NRP1 interaction are scarce. Herein, we describe the identification of 1, a novel nonpeptide small-molecule NRP1 antagonist with moderate activity via structure-based virtual screening. Ensemble docking and molecular dynamics (MD) simulations of 1 were carried out and an interesting binding model was obtained. We found that the "aromatic box" enclosed by Tyr297, Trp301 and Tyr353 of NRP1 is critical for NRP1-1 binding. Further structure modification of 1 based on the binding model derived from MD simulations resulted in the identification of 12a with significantly improved activity.
血管内皮生长因子（VEGF）-神经纤毛蛋白 1（NRP1）相互作用的多方面作用已被牵涉到癌症中，但关于 VEGF-NRP1 相互作用的小分子抑制剂的报道却很少。在此，我们通过基于结构的虚拟筛选，描述了新型非肽类小分子 NRP1 拮抗剂 1 的鉴定，其具有中等活性。我们对 1 进行了组合 docking 和分子动力学（MD）模拟，并获得了一个有趣的结合模型。我们发现 NRP1 的 Tyr297、Trp301 和 Tyr353 所围成的“芳环盒”对于 NRP1-1 的结合至关重要。进一步基于 MD 模拟得出的结合模型对 1 进行结构修饰，得到了活性显著提高的 12a。
