Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation

Abstract

Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC value of 22.32 µM and a K value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor. Compound 8 was tested against A-549 tumor cell lines with IC value of 17.8 µM. To investigate the intermolecular interaction of Wee1 and compound 8, further molecular dynamics simulations were performed. It indicates that the binding mode of compound 8 and reference ligand is similar. The active core scaffold of compound 8 could represent a promising lead compound for studying Wee1 and be used for further structural optimization to design more potent Wee1 inhibitors.

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

“…137 5) were identified. 141 In the same year, Hu et al screened the ZINC database via ligand-based pharmacophore modeling and identified eight potential ligands with new scaffolds, which were further subjected to QSAR, ADMET, and binding free energy studies followed by molecular dynamics (MD) simulations and ultimately proposed 3 (Figure 5) as a potent WEE1i. 142 Furthermore, vanillates (4) (Figure 5) have also exhibited micromolar WEE1 inhibition and were initially treated as an important class of WEE1i.…”

“…159 In contrast, compound libraries containing glutarimide-structural frag-ments were synthesized and screened for compounds promoting the ubiquitination of WEE1. WX106 (141), a CRBN competitive binder, induced the desired proteasomedependent degradation of WEE1 and is effective against 18 cell lines tested. 161 The toxicity of AZD1775 is a result of off-target and on-target inhibition, but the corresponding PROTACs offer ample selectivity and probably no off-target toxicity and tolerable on-target toxicity.…”

“…Later in 2019, via ensemble docking of 20 WEE1 crystal structures, two new ligands 1 and 2 ( Figure 5 ) were identified. 141 In the same year, Hu et al screened the ZINC database via ligand-based pharmacophore modeling and identified eight potential ligands with new scaffolds, which were further subjected to QSAR, ADMET, and binding free energy studies followed by molecular dynamics (MD) simulations and ultimately proposed 3 ( Figure 5 ) as a potent WEE1i. 142 Furthermore, vanillates ( 4 ) ( Figure 5 ) have also exhibited micromolar WEE1 inhibition and were initially treated as an important class of WEE1i.…”

“…Li et al in 2018 performed pharmacophore modeling, docking, and MD simulations and identified a new scaffold ( XVI ) having an IC 50 value of 22.32 μM against WEE1 and an IC 50 value of 17.8 μM when tested against A-549 cell lines. 153 Pyridothienopyrimidine ( XVI ) is synthesized by cyclization of pyridothiophene 130 with hydrazine, followed by reacting with bromophenylethanone ( 132 ) via forming an intermediate 131 ( Scheme 26 ). 154 …”

N1-(3-(Trifluoromethyl)Phenyl) Isophthalamide Derivatives as Promising Inhibitors of Vascular Endothelial Growth Factor Receptor: Pharmacophore-Based Design, Docking, and MM-PBSA/MM-GBSA Binding Energy Estimation

“…In this context, the recent advances in the development of molecular modeling techniques for the search of biologically active compounds cannot be overlooked. The literature describes cases of successful application of pharmacophore screening [28,29], molecular docking, and molecular dynamics [30][31][32] to identify new chemical structures with anti-kinase activity. In addition, the improvements in technical and theoretical background of machine learning algorithms have made it possible to adapt them, inter alia, for the modeling of protein-ligand interactions [33][34][35][36].…”