基于虚拟筛选策略发现新型潜在JAK3小分子抑制剂

Discovery of Novel Potential JAK3 Small Molecule Inhibitors Based on Virtual Screening Strategy

利用已知活性的分子采用基于配体的策略构建药效团模型,通过基于类药规则、药效团模型、多种精度的分子对接算法、MM/GBSA结合能预测以及ADMET筛选手段对含约250万个分子的数据库进行虚拟筛选。发现5种JAK3抑制剂的新型骨架,其中6个以1-苯基咪唑烷-2-酮为骨架的分子在与JAK3激酶的结合能以及分子的ADMET性质评价方面均表现优异,具备高JAK3抑制剂潜力,被认为是虚拟筛选的命中分子。

The pharmacophore model is constructed by using the known active molecules and the ligand based strategy. The database containing about 2.5 million molecules is virtual screened by means of drug like rules, pharmacophore model, multiple precision molecular docking algorithms, MM/GBSA binding energy prediction and ADMET screening. The novel skeletons of five JAK3 inhibitors were found. Among them, six molecules with 1-phenylimidazolidine-2-one as the skeleton showed excellent performance in binding energy with JAK3 kinase and ADMET property evaluation. They had the potential to be developed as a highly active JAK3 inhibitor, and were considered as hit molecules for virtual screening.