Computational simulation studies on the binding selectivity of Wee1 and Checkpoint kinase 1 by molecular dynamics simulation combined with free energy calculations.

Wee1 kinase and Checkpoint kinase 1 (Chk1) kinase, which are well known to be involved in cancer, are promising targets for cancer therapy. Most of developed Wee1 inhibitors can inhibit activity of Chk1 kinase to different degrees as well. The poor selectivity brought side effects and selective inhibitor is needed. However, the selective mechanisms of Wee1 versus Chk1 are not clear. Therefore, the design of selective Wee1 and Chk1 inhibitors would provide a meaningful starting for the development of anticancer drugs with optimal efficacy. In this study, Wee1 inhibitors with different selectivity over Chk1 were chosen to analyze the selectivity mechanism by means of molecular docking, molecular dynamics simulations and binding free energy calculations. Two key residues of Wee1 kinase and two critical residues of Chk1 were mutated to detect their effect on ligand binding into protein. The results indicated that these residues play a pivotal role in the binding interactions of ligands to receptors through hydrogen bond and hydrophobic interaction with inhibitors. This may provide a better understanding of the selective mechanism of Wee1 and Chk1. It would be beneficial to the discovery and optimization of selective Wee1 and Chk1 inhibitors.Communicated by Ramaswamy H. Sarma.