Ensemble docking-based virtual screening toward identifying inhibitors against Wee1 kinase.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Wee1 kinase is crucial for the G2/M cell cycle checkpoint, preventing mitosis upon DNA damage.
• Targeting Wee1 kinase is a promising strategy for cancer therapy, particularly for enhancing chemotherapy efficacy.

Purpose of the Study:

• To discover novel and potent inhibitors of Wee1 kinase.
• To identify compounds that can be optimized for anticancer drug development.

Main Methods:

• Virtual screening using ensemble docking with multiple crystal structures.
• Evaluation of 17 scoring functions from various docking software for molecular docking accuracy.
• In vitro assays to determine inhibitory concentrations (IC50) and cell viability.

Main Results:

• Two novel compounds, designated B1 and A2, were identified as effective Wee1 inhibitors.
• Compound B1 showed an IC50 of 10.23 ± 0.505 μM, and compound A2 showed an IC50 of 8.72 ± 0.323 μM.
• Both compounds demonstrated significant anticancer activity in cell viability assays.

Conclusions:

• The identified compounds B1 and A2 represent a valuable starting point for developing more potent Wee1 inhibitors.
• Further structural optimization of these compounds could lead to novel anticancer therapeutics.
• This study validates ensemble docking as an effective strategy for discovering kinase inhibitors.