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Identification of potent TMPRSS4 inhibitors through structural modeling and molecular dynamics simulations
Ismail Hdoufane1, Mehdi Oubahmane2, Youssef Habibi3
1Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Cadi Ayyad University, BP 2390, 40000, Marrakech, Morocco. i.hdoufane@uca.ac.ma.
Scientific Reports
|January 21, 2025
Summary
Researchers identified potential inhibitors for Transmembrane Serine Protease 4 (TMPRSS4), a protein linked to viral infections and cancer. Computational methods revealed Ergotamine and other compounds show strong binding affinity, suggesting they could be effective TMPRSS4 inhibitors.
Area of Science:
- Biochemistry
- Drug Discovery
- Computational Biology
Background:
- Transmembrane Serine Protease 4 (TMPRSS4) is implicated in various pathologies, including activating SARS-CoV-2 and promoting cancer progression.
- TMPRSS4's role in disease necessitates the identification of novel inhibitors with superior binding affinity compared to existing ones like 2-hydroxydiarylamide and tyroserleutide.
Purpose of the Study:
- To discover novel TMPRSS4 inhibitors with enhanced binding affinity.
- To develop and validate structural models of the TMPRSS4 serine protease domain for drug screening.
Main Methods:
- 3D structural modeling of the TMPRSS4 serine protease domain.
- Molecular dynamics (MD) simulations and molecular mechanics with generalized Born surface area (MM-GBSA) calculations.
- Molecular docking of FDA-approved drugs, clinical/preclinical candidates, and natural products.
Main Results:
- Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 demonstrated high stability and strong binding affinity with TMPRSS4.
- Ergotamine exhibited the most favorable binding energy (-33.73 kcal/mol).
- Low RMSD and RMSF values indicated stable drug-protein complexes.
Conclusions:
- The identified compounds, particularly Ergotamine, show promise as potent TMPRSS4 inhibitors.
- These in silico findings warrant further experimental validation to confirm their therapeutic potential.
