Computational insights into inhibiting EphA2: Integrating structure-based virtual screening, docking, and molecular...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Ephrin type A receptor-2 (EphA2) is frequently overexpressed and dysfunctional in various cancers, correlating with disease progression and poor prognosis.
• Targeting EphA2 with small-molecule inhibitors presents a promising therapeutic strategy to counteract cancer development and metastasis.

Purpose of the Study:

• To identify novel, potent, and selective small-molecule inhibitors of EphA2 using structure-based virtual screening.
• To evaluate the binding affinity and stability of candidate inhibitors through molecular docking and simulations.

Main Methods:

• Structure-Based Virtual Screening (SBVS) was performed using the Mcule database and drug similarity filters.
• Compounds were filtered for toxicity and ADME standards, followed by multi-scoring docking assessments using Mcule Single Click, DockThor, and SwissDock.
• Molecular Dynamics (MD) simulations were conducted on top-ranked compounds, including dasatinib, to analyze stability and binding free energy.

Main Results:

• Virtual screening identified several potent EphA2 inhibitors, with four novel small molecules (Mcule-1579910267, Mcule-1893218381, Mcule-3981378344, Mcule-8617639093) exhibiting binding affinities comparable to or exceeding the known inhibitor dasatinib.
• Mcule-8617639093 demonstrated significant stability during MD simulations, indicated by RMSD, RMSF, SASA, ΔGsolv, and Rg analyses.
• The identified compounds show strong binding free energy (ΔG) values, with novel molecules achieving up to -9.3 kcal/mol.

Conclusions:

• Novel small molecules, particularly Mcule-8617639093, exhibit potent and stable binding to EphA2, suggesting their potential as selective inhibitors.
• These findings provide a strong foundation for the development of new targeted therapies against EphA2-driven cancers.