靶向FLT3的抗肿瘤小分子抑制剂的虚拟筛选  

Virtual Screening of Small Molecule Inhibitors Targeting FLT3 forAntitumor Activity

作　　者：魏晓哲 张宇[1] 史继文 闫红[1] 钟启迪 WEI Xiao-zhe;ZHANG Yu;SHI Ji-wen;YAN Hong;ZHONG Qi-di(College of Chemistry and Life Sciences,Beijing University of Technology,Beijing,100124,China;College of Pharmacy,North China University of Science and Technology,Tangshan,Hebei,063210,China)

机构地区：[1]北京工业大学化学与生命科学学院,北京100124 [2]华北理工大学药学院,河北唐山063210

出　　处：《现代生物医学进展》2024年第22期4201-4206,共6页Progress in Modern Biomedicine

基　　金：河北省自然科学基金项目(C2020209081)。

摘　　要：目的:本研究旨在利用虚拟筛选技术,从ChEMBL数据库中发现新型FLT3抑制剂,为靶向FLT3的小分子抑制剂的开发提供理论基础。方法:选取ChEMBL数据库中约240万个小分子作为数据集,以FLT3蛋白为靶标,通过分子对接进行虚拟筛选,对筛选得到的目标化合物进行200 ns的分子动力学模拟,研究其与FLT3蛋白之间的结合能力和稳定性。结果:通过虚筛选成功发现了5个未见文献报道的新型潜在FLT3抑制剂(ChEMBL ID:5186572、4845881、2151842、3642822、3916042),对接分数(-10.93~-12.58)和结合自由能(-82.06~-88.49 kcal/mol)均优于参照组Gilteritinib(-8.73和-65.38 kcal/mol);分子动力学模拟结果显示,目标化合物与FLT3蛋白均具有较强的结合能力,且与FLT3蛋白形成的复合物具有良好的稳定性。结论:本研究利用虚拟筛选技术成功发现了5个未见文献报道的具有潜在抗肿瘤活性的FLT3抑制剂,为新一代FLT3抑制剂的研发提供了重要的理论基础。Objective:To discover novel FLT3 inhibitors from the ChEMBL database by using virtual screening technology,and provide a theoretical foundation for the development of small molecule inhibitors targeting FLT3.Methods:Approximately 2.4 million small molecules from the ChEMBL database were selected as the dataset.FLT3 protein was chosen as the target,and virtual screening was conducted via molecular docking.The binding affinity and stability of target compounds with FLT3 protein were investigated by using 200 ns of molecular dynamics simulation.Results:Five novel potential FLT3 inhibitors(ChEMBL ID:5186572,4845881,2151842,3642822,3916042)not previously reported in the literature were successfully discovered by virtual screening.The docking scores(-10.93 to-12.58)and binding free energies(-82.06 to-88.49 kcal/mol)of these compounds were superior to the reference compound Gilteritinib(-8.73 and-65.38 kcal/mol).The results of molecular dynamics simulation have demonstrated a strong binding affinity of the target compounds with FLT3 protein,leading to the formation of stable complexes.Conclusion:Five novel potential FLT3 inhibitors with potential anti-tumor activity not previously reported were discovered by virtual screening technology.These findings provide an important theoretical foundation for the development of next-generation FLT3 inhibitors.

关 键 词：FLT3抑制剂 急性髓系白血病 分子对接 虚拟筛选 分子动力学模拟 

分 类 号：R733.71[医药卫生—肿瘤] Q78[医药卫生—临床医学]