化学
细胞周期蛋白依赖激酶1
数量结构-活动关系
分子模型
生物化学
生物信息学
组合化学
计算生物学
立体化学
体外
对接(动物)
细胞周期
细胞
生物
基因
护理部
医学
作者
Abdulkarim Najjar,Charlott Platzer,Anton Luft,Chris Aßmann,Nehal H. Elghazawy,Frank Erdmann,Wolfgang Sippl,Karin Schmidtkunz
标识
DOI:10.1016/j.ejmech.2018.10.050
摘要
In the current work, we applied computational methods to analyze the membrane-associated inhibitory kinase PKMYT1 and small molecule inhibitors. PKMYT1 regulates the cell cycle at G2/M transition and phosphorylates Thr14 and Tyr15 in the Cdk1-cyclin B complex. A combination of in silico and in vitro screening was applied to identify novel PKMYT1 inhibitors. The computational approach combined structural analysis, molecular docking, binding free energy calculations, and quantitative structure–activity relationship (QSAR) models. In addition, a computational fragment growing approach was applied to a set of previously identified diaminopyrimidines. Based on the derived computational models, several derivatives were synthesized and tested in vitro on PKMYT1. Novel inhibitors active in the sub-micromolar range were identified which provide the basis for further characterization of PKMYT1 as putative target for cancer therapy.
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