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ID: ALA4325875
Journal: Eur J Med Chem
Title: Computer-aided design, synthesis and biological characterization of novel inhibitors for PKMYT1.
Authors: Najjar A, Platzer C, Luft A, Aßmann CA, Elghazawy NH, Erdmann F, Sippl W, Schmidt M.
Abstract: 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.
CiteXplore: 30388464