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Updated: Jan 9, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
Carmen Ortiz-González1, Berta Casar2, Rafael Gozalbes1,3
1MolDrug AI Systems SL, Parque Tecnológico de Valencia, 46980 Valencia, Spain.
Abstract:
Protein-protein interactions (PPIs) take place in many cellular processes, including the activation of cellular cascades, such as the MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular-Regulated Kinase) pathway. Deregulation of these pathways leads to the development of diseases, such as cancer. DEL-22379 is an ERK2 dimerization inhibitor, which presents anti-tumoral effects, without affecting ERK2 phosphorylation. Our aim was to identify new therapeutic molecules targeting ERK2 dimerization, based on DEL-22379 structure. In this study, we implemented a combination of computational and experimental workflow, which includes in silico techniques, such as scaffold hopping and virtual screening to generate a dataset of candidate compounds, a native PAGE (PolyAcrylamide Gel Electrophoresis) electrophoresis to experimentally screen the potential inhibitors, and a detailed molecular docking and chemical profile prediction to understand the potential mechanism of action of the selected compounds. From an initial dataset of 536 compounds, we obtained two hit molecules that exhibited inhibitory effects on ERK2 dimerization: Drug73 and Drug120. A computational analysis of the mechanism of action, unveiled that Drug73 and Drug120 presented an improved docking score, and better drug-like properties when compared to DEL-22379. This study shows that computational studies, in combination with experimental evaluation, can be useful and efficient to find new therapeutic compounds.
Insights
Researchers identified new potential cancer drugs by inhibiting ERK2 dimerization. Computational and experimental methods revealed two promising molecules, Drug73 and Drug120, offering improved properties over existing inhibitors.
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.
