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Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. In order to discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good PLS statistics (R= 0.9212, Q= 0.7457), was selected and validated. The validated model was used as a 3D search query for databases virtual screening. The filtered molecules were further analyzed and refined by Lipinski's rule of 5, multiple docking procedures (HTVS, SP, GOLD, XP and unique QPLD, that is, quantum polarized ligand docking), ADMET screening and the Prime/MM-GBSA method binding free energy calculations. Eight leads were identified as potential Wee1 inhibitors, and a 50 ns molecular dynamics (MD) simulation was carried out for top four inhibitors to predict the stability of ligand-protein complex. MM-PBSA based on MD simulation and the energy contribution per residue to the binding energy was calculated. In the end, three hits with good stabilization and affinity to protein were identified.

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