基于分子对接研究吲哚咔唑类小分子对Tie-2/VEGFR2的双效抑制作用模式*

 运用分子对接技术研究了吲哚咔唑类小分子对人血管内皮生长因子受体2(VEGFR2)和人血管生成素受体Tie-2(ANG-R-Tie-2)的双效抑制作用模式。研究结果表明，吲哚咔唑类小分子的双效抑制作用主要源于两种受体相似的活性口袋，小分子与两者的铰链区均可形成氢键，使其催化活性受到抑制，从而抑制肿瘤细胞的生长。抑制活性的差异主要源于活性口袋的细微差异所导致疏水、静电等相互作用的不同。其中，疏水作用的差异是影响配体选择性的主要原因，静电作用、氢键及空间位阻对结合稳定也有一定影响。该文的研究结果为多靶点酪氨酸激酶小分子抑制剂的设计及提高激酶抑制剂的选择性提供了重要的理论依据。

Studies on Interactions between Tie-2/VEGFR2 and Dihydroindazolocarbazole Dual Inhibitors via Molecular Docking

Dihydroindazolocarbazoles(DHI-carbazoles) are the potent dual inhibitors to VEGFR2 and Tie-2.In this work,the mechanism of interaction between VEGFR2/Tie-2 and DHI-carbazoles was performed with Surflex-dock.The results from molecular docking indicated that DHI-carbazoles competitively bound to the active site,which was the substrate ATP in VEGFR2/Tie-2 with high affinity.The differences of activity between VEGFR2 and Tie-2 resulted from the minor difference of active pockets.Hydrophobic effect played a key role in the formation and stability.Hydrogen bond and electrostatic effect also contributed to the difference.This work elucidated the antitumor mechanism of the DHI-carbazoles as a dual potent inhibitor and provided theoretical basis for the design of tyrosine kinase inhibitors.