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Updated: Sep 23, 2025
Author Spotlight: Advancing Antiviral Strategies Through Novel Immunocapture and Mass Spectrometry Techniques
Published on: January 12, 2024
Hybrid drug-screening strategy identifies potential SARS-CoV-2 cell-entry inhibitors targeting human transmembrane
Yufei Feng1, Xiaoning Cheng2, Shuilong Wu2
1Life Science and Technology School, Lingnan Normal University, Zhanjiang, 524048 Guangdong Province China.
Abstract:
The spread of coronavirus infectious disease (COVID-19) is associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has risked public health more than any other infectious disease. Researchers around the globe use multiple approaches to identify an effective approved drug (drug repurposing) that treats viral infections. Most of the drug repurposing approaches target spike protein or main protease. Here we use transmembrane serine protease 2 (TMPRSS2) as a target that can prevent the virus entry into the cell by interacting with the surface receptors. By hypothesizing that the TMPRSS2 binders may help prevent the virus entry into the cell, we performed a systematic drug screening over the current approved drug database. Furthermore, we screened the Enamine REAL fragments dataset against the TMPRSS2 and presented nine potential drug-like compounds that give us clues about which kinds of groups the pocket prefers to bind, aiding future structure-based drug design for COVID-19. Also, we employ molecular dynamics simulations, binding free energy calculations, and well-tempered metadynamics to validate the obtained candidate drug and fragment list. Our results suggested three potential FDA-approved drugs against human TMPRSS2 as a target. These findings may pave the way for more drugs to be exposed to TMPRSS2, and testing the efficacy of these drugs with biochemical experiments will help improve COVID-19 treatment.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s11224-022-01960-w.
Insights
Researchers screened approved drugs and molecular fragments targeting TMPRSS2 to block SARS-CoV-2 entry. Three FDA-approved drugs were identified as potential treatments for COVID-19, offering new avenues for drug repurposing.
Area of Science:
- Biochemistry
- Drug Discovery
- Virology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a significant global health threat.
- Drug repurposing is a key strategy to find effective treatments for viral infections.
- Most research targets spike protein or main protease, but transmembrane serine protease 2 (TMPRSS2) is a novel target.
Purpose of the Study:
- To identify approved drugs and molecular fragments that bind to TMPRSS2, inhibiting SARS-CoV-2 entry.
- To provide insights for structure-based drug design against COVID-19.
- To validate potential drug candidates using computational methods.
Main Methods:
- Systematic drug screening of approved drug databases.
- Screening of the Enamine REAL fragments dataset against TMPRSS2.
- Molecular dynamics simulations, binding free energy calculations, and well-tempered metadynamics.
- Identification of potential drug-like compounds and FDA-approved drugs.
Main Results:
- Nine potential drug-like compounds were identified from fragment screening.
- Three FDA-approved drugs were suggested as potential inhibitors of human TMPRSS2.
- Computational validation confirmed the efficacy of candidate drugs and fragments.
Conclusions:
- Targeting TMPRSS2 is a viable strategy for developing COVID-19 therapeutics.
- The identified compounds and drugs may serve as starting points for further investigation.
- Biochemical validation of these candidates could advance COVID-19 treatment options.
