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

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Wee1 kinase is crucial for G2/M cell cycle arrest, enabling DNA repair before mitosis.
• Overexpression of Wee1 is frequently observed in various cancer cells, making it a potential therapeutic target.

Purpose of the Study:

• To identify novel Wee1 inhibitors using computational and experimental approaches.
• To characterize the inhibitory potential and binding interactions of a newly discovered compound against Wee1.

Main Methods:

• Utilized pharmacophore modeling, molecular docking, and molecular dynamics simulations.
• Performed kinetic assays to determine the inhibition type and IC50 values.
• Evaluated compound efficacy against A-549 lung cancer cell lines.

Main Results:

• Identified compound 8 with a novel scaffold, exhibiting an IC50 of 22.32 µM and Ki of 13.11 µM against Wee1.
• Compound 8 demonstrated competitive inhibition kinetics.
• Showed an IC50 of 17.8 µM against A-549 tumor cells.
• Molecular dynamics simulations revealed a binding mode similar to reference ligands.

Conclusions:

• Compound 8 represents a promising lead for developing potent Wee1 inhibitors.
• Its novel scaffold warrants further structural optimization for enhanced anticancer efficacy.
• This study provides a foundation for new therapeutic strategies targeting Wee1 in cancer.