Identification of FDA-Approved Drugs as Potential Inhibitors of WEE2: Structure-Based Virtual Screening and Molecular...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Biology

Background:

• Wee1-like protein kinase 2 (WEE2) is crucial for oocyte maturation and fertilization.
• WEE2 is a selective target for reproductive health due to its restricted expression.
• No approved WEE2 modulators currently exist for clinical use.

Purpose of the Study:

• To identify potential WEE2 inhibitors using an integrated in silico approach.
• To screen repurposed drug candidates for WEE2 inhibitory activity.
• To evaluate the binding affinity and stability of identified compounds.

Main Methods:

• Structure-based virtual screening of ~3800 DrugBank compounds.
• Molecular dynamics (MD) simulations for 300 ns.
• MM-PBSA free-energy calculations and docking analyses.

Main Results:

• Ten high-affinity WEE2 inhibitors were identified, with Midostaurin and Nilotinib showing the most promise.
• Both compounds exhibited strong binding affinities and interaction patterns similar to known inhibitors.
• MD simulations confirmed stable protein-ligand complexes and ligand-induced stabilization of WEE2.

Conclusions:

• Midostaurin and Nilotinib are promising repurposed drug candidates for WEE2 modulation.
• The study validates an in silico pipeline integrating MD and ML/DL for drug discovery.
• This approach can accelerate the identification and prioritization of compounds for in vitro testing.