Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• Protein-protein interactions (PPIs) are crucial for cellular processes, including the MAPK/ERK pathway.
• Dysregulation of the MAPK/ERK pathway is linked to cancer development.
• DEL-22379 is an ERK2 dimerization inhibitor with anti-tumoral effects.

Purpose of the Study:

• To identify novel therapeutic molecules targeting ERK2 dimerization based on the DEL-22379 structure.
• To explore new drug candidates for cancer therapy by inhibiting ERK2 dimerization.

Main Methods:

• Utilized a combined computational and experimental workflow.
• Employed in silico techniques: scaffold hopping and virtual screening.
• Experimental screening using native PAGE electrophoresis and molecular docking.

Main Results:

• Generated a dataset of 536 candidate compounds.
• Identified two hit molecules, Drug73 and Drug120, with ERK2 dimerization inhibitory effects.
• Drug73 and Drug120 demonstrated improved docking scores and drug-like properties compared to DEL-22379.

Conclusions:

• Computational studies combined with experimental validation are effective for discovering new therapeutic compounds.
• Drug73 and Drug120 represent promising leads for developing novel ERK2 dimerization inhibitors.
• This approach can accelerate the identification of potential anti-cancer agents targeting specific PPIs.