| 杨婷,付磊,李燕楠,等.基于药效团和分子对接的FLT3抑制剂筛选方法（英文）[J].中国海洋药物,2023,42(3):10-22. |
| 基于药效团和分子对接的FLT3抑制剂筛选方法（英文） |
| Pharmacophore Modeling and Molecular Docking based method for screening FLT3 inhibitors |
| 投稿时间：2022-03-02 修订日期：2022-04-18 |
| DOI：10.13400/j.cnki.cjmd.2023.03.011 |
| 中文关键词: 急性髓系白血病 FLT3-ITD 3-苯基吡唑并[1,5-a]嘧啶骨架 分子对接 海洋药物 |
| English Keywords:AML FLT3-ITD 3-phenylpyrazolo[1,5-a]pyrimidine scaffold molecular docking Marine durgs |
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| 中文摘要: |
| 目的 建立虚拟筛选与生物检测相结合的方法来筛选FLT3抑制剂。方法 建立了基于药效团和对接的虚拟筛选方法用于筛选靶向FLT3的化合物，并建立FLT3-ITD过表达的细胞模型进一步验证抑制剂的药效及作用机制。结果 通过筛选商业化合物库，成功发现了1个含有3-苯基吡唑并[1,5-a]嘧啶骨架的化合物（命名74），可以选择性地抑制表达FLT3-ITD的BaF3细胞和AML细胞增殖。进一步研究表明，在细胞实验中，74也能克服FLT3-ITD -D835V、-D835Y、-F691L、-N676K等二次突变。机制研究表明，74通过抑制FLT3介导的通路抑制AML细胞的生长。结论 74是1个潜在的抑制FLT3-ITD的苗头分子，它的发现验证了FLT3筛选方法的准确性，并可用来寻找海洋来源的FLT3抑制剂。 |
| English Summary: |
| Objective To develop the method of virtual screening coupled with biological detection for screening FLT3 inhibitors. Methods The pharmacophore- and docking-based screening methods were developed for virtualy screening the hits targeting FLT3, and FLT3-ITD overexpressing cellular models for further verifying the inhibitory effect and its related mechanism. Results By screening the commercial library, a compound harboring scaffold of 3-phenylpyrazolo[1,5-a]pyrimidine, namely 74 was successfully discovered, which selectively inhibited the proliferation of FLT3-ITD expressing BaF3 cells and AML cells. Further study indicated that compound 74 could also overcome secondary mutations, including FLT3-ITD -D835V, -D835Y, -F691L, -N676K mutations in cellular assays. Mechanically, compound 74 inhibited the growth of AML cells by suppressing FLT3 mediated pathway. Conclusion The results indicated that compound 74 is a promising hit for FLT3-ITD inhibition. The discovery of compound 74 validated the screening methods, which can be further used to find marine-derived FLT3 inhibitors. |
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