Semaxanib (SU5416) and 3-[4′-fluorobenzylidene]indolin-2-one (SU5205) are structurally similar drugs that are able to inhibit vascular endothelial growth factor receptor-2 (VEGFR2), but the former is 87 times more effective than the latter. Previously, SU5205 was used as a radiolabelled inhibitor (as surrogate for SU5416) and a radiotracer for positron emission tomography (PET) imaging, but the compound exhibited poor stability and only a moderate IC₅₀ toward VEGFR2. In the current work, the relationship between the structure and activity of these drugs as VEGFR2 inhibitors was studied using 3D-QSAR, docking and molecular dynamics (MD) simulations. First, comparative molecular field analysis (CoMFA) was performed using 48 2-indolinone derivatives and their VEGFR2 inhibitory activities. The best CoMFA model was carried out over a training set including 40 compounds, and it included steric and electrostatic fields. In addition, this model gave satisfactory cross-validation results and adequately predicted 8 compounds contained in the test set. The plots of the CoMFA fields could explain the structural differences between semaxanib and SU5205. Docking and molecular dynamics simulations showed that both molecules have the same orientation and dynamics inside the VEGFR2 active site. However, the hydrophobic pocket of VEGFR2 was more exposed to the solvent media when it was complexed with SU5205. An energetic analysis, including Embrace and MM-GBSA calculations, revealed that the potency of ligand binding is governed by van der Waals contacts.

Semaxanib（SU5416）和3- [4'-氟亚苄基]吲哚-2-酮（SU5205）是结构相似的药物，能够抑制血管内皮生长因子受体2（VEGFR2），但前者的功效是其的87倍后者。以前，SU5205用作放射性标记的抑制剂（作为SU5416的替代物）和用于正电子发射断层扫描（PET）成像的放射性示踪剂，但该化合物显示出较差的稳定性且仅具有中等的IC ₅₀对VEGFR2。在当前的工作中，使用3D-QSAR，对接和分子动力学（MD）模拟研究了作为VEGFR2抑制剂的这些药物的结构与活性之间的关系。首先，使用48种2-吲哚酮衍生物及其对VEGFR2的抑制活性进行了比较分子场分析（CoMFA）。最佳的CoMFA模型是在包含40种化合物的训练集中进行的，其中包括空间和静电场。此外，该模型提供了令人满意的交叉验证结果，并充分预测了测试集中包含的8种化合物。CoMFA场的图可以解释semaxanib和SU5205之间的结构差异。对接和分子动力学模拟表明，两种分子在VEGFR2活性位点内具有相同的方向和动力学。然而，当VEGFR2与SU5205复合时，其疏水口袋更暴露于溶剂介质。包括Embrace和MM-GBSA计算在内的高能分析表明，配体结合的效力受范德华接触的支配。