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Updated: May 5, 2026
Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
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.
Abstract:
TMPRSS4, a transmembrane serine protease type II, is associated with various pathological illnesses. It has been found to activate SARS-CoV-2, enhance viral infection of human small-intestinal enterocytes and is overexpressed in different types of cancers. Therefore, this study aims to disover potential TMPRSS4 inhibitors that have better binding affinity than the approved inhibitors: 2-hydroxydiarylamide and tyroserleutide. Since no 3D-structure is known for TMPRSS4, structural models for the TMPRSS4 serine protease domain were developed. The modeled structures were validated and subjected to molecular dynamics simulations. FDA-approved, clinical/preclinical drugs and natural products were docked to the pocket of TMPRSS4. Moreover, through a systematic analysis, MD simulations and MM-GBSA binding free energy calculations revealed that the best candidates Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 are highly stable drug candidates in complex with TMPRSS4, displaying low RMSD and RMSF values with strong binding stability. Among these compounds, Ergotamine showed the most favorable binding energy (-33.73 kcal/mol). Overall, our in silico results revealed that these compounds could act as potent TMPRSS4 inhibitors and need to be validated by future experimental studies.
Insights
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.
