| 曾巧玲,刘鹰翔,李耿,马玉卓.化学通报,2019,82(10):917-925. |
| 二氢嘧啶并[4,5-d]嘧啶类衍生物作为CSF-1R激酶抑制剂的分子对接和定量构效关系研究 |
| Studies on Molecular Docking and QSAR of Dihydropyrimido [4,5-d] pyrimidine Derivatives as CSF-1R Inhibitors |
| 投稿时间：2019-06-30 修订日期：2019-08-05 |
| DOI： |
| 中文关键词: 集落刺激因子-1受体（CSF-1R） 分子对接 三维定量构效关系模型 二氢嘧啶并[4,5-d]嘧啶类衍生物 |
| 英文关键词:CSF-1R Molecular docking 3D-QSAR model Dihydropyrimido[4,5-d]pyrimidine derivatives |
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| 中文摘要: |
| 集落刺激因子-1受体激酶（CSF-1R）属于Ⅲ型受体酪氨酸激酶家族成员，其在调控单核巨噬细胞系中发挥重要作用。CSF-1R及其配体异常表达与肿瘤发展过程密切相关。因此，CSF-1R信号传导可成为抗肿瘤治疗的有吸引力的靶标。本文用比较分子场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）研究了54个二氢嘧啶并[4,5-d]嘧啶类CSF-1R激酶抑制剂的三维定量构效关系（3D-QSAR）。基于配体叠合，CoMFA和CoMSIA模型的交叉验证系数（q2）分别为0.725和0.636，拟合验证系数（r2）分别为0.960和0.958，结果表明这两种模型均具有较好的预测能力。所建模型的等势图能直观反映分子不同取代基对活性的影响，其中立体场和疏水场对活性的贡献较大。通过分子对接研究显示，氨基酸残基Cys666、Asp796在配体和受体结合过程中产生作用，分子对接的结合模式与3D-QSAR得到的结果一致。这些信息为进一步优化CSF-1R激酶抑制剂提供了理论基础。 |
| 英文摘要: |
| Colony stimulating factor 1 receptor (CSF-1R) is a member of the type Ⅲ receptor tyrosine kinase family, which plays a crucial role in the regulation of the monocyte/macrophage system. Abnormal expression of CSF-1R and its ligands is closely related to tumor progression. Therefore, CSF-1R signaling might be an effective target for anti-cancer therapy. In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR) models were generated for 54 dihydropyrimido [4,5-d] pyrimidine CSF-1R inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The cross-validation coefficient (q2) of the CoMFA model and CoMSIA model were 0.725 and 0.636, and the fitting verification coefficients (r2) were 0.960 and 0.958. The results showed that both models have good predictive ability. The contour maps of the models could visually reflect the effect of different substituents on the activity, and the stereo field and the hydrophobic field contributed more to the activity. The molecular docking study showed that the amino acid residue Cys666 and Asp796 play a role in the ligand-receptor binding process, and the molecular docking binding mode is consistent with the results obtained by 3D-QSAR. The information could provid a theoretical basis for further optimization of this class CSF-1R inhibitors. |
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