噻吩并嘧啶类FLT3抑制剂结合模式预测与分析

FLT3(FMS样酪氨酸酶III)是酪氨酸激酶受体(RTKIII)成员之一,其异常超表达或突变与急性髓细胞白血病(AML)呈现非常大的相关性,成为治疗AML的重要靶位点。本文采用不同的方法对FLT3活性位点进行了预测,利用分子对接、分子动力学以及药效团分析研究了新型嘧啶类化合物与FLT3的相互作用与结合模式。分子对接得到的结合模式与分子动力学模拟得到的结果一致,结合药效团分析表明该嘧啶类化合物主要通过疏水相互作用和氢键与FLT3激活位点结合,从而起到抑制作用。本研究对以FLT3为靶点的嘧啶类抑制剂的开发提供了理论和实验依据。

Prediction and Analysis of Thienopyrimidine-based FLT3 Inhibitors Binding Mode

as a member of the receptor tyrosine kinase III family (RTKIII), FLT3 (FMS-like receptor tyrosine kinase-3) plays a key role in hematopoiesis, and its abnormal over-expression or mutation is found to be closely related to acute myeloid leukemia (AML), thus becoming the main target for treating AML. In this study, the interaction modes between 10 thienopyrimidine-based FLT3 inhibitors and the protein were investigated by different methods as protein-ligand binding site predictions, molecular docking, molecular dynamics simulation and pharmacophore studies. By analysis, results from molecular docking are in consistency with that obtained by molecular dynamics simulation. Combined with the results of pharmacophore analysis, it shows that hydrophobic interaction as well as the hydrogen bonds are playing the driven role for pyrimidine-like compounds exerting inhibitory effects on the FLT3 protein. It was expected that this study could be helpful for the AML-targeting drug design and discovery in future.