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Updated: Dec 2, 2025
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Unravelling high-affinity binding compounds towards transmembrane protease serine 2 enzyme in treating SARS-CoV-2
Pooja M1, Gangavaram Jyothi Reddy2, Kanipakam Hema3
1Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam (Women's University), Tirupati, 517502, Andhra Pradesh, India.
Abstract:
The coronavirus disease-19 (COVID-19) outbreak that is caused by a highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a zoonotic pandemic, with approximately 24.5 million positive cases and 8.3 lakhs deaths globally. The lack of effective drugs or vaccine provoked the research for drug candidates that can disrupt the spread and progression of the virus. The identification of drug molecules through experimental studies is time-consuming and expensive, so there is a need for developing alternative strategies like in silico approaches which can yield better outcomes in less time. Herein, we selected transmembrane protease serine 2 (TMPRSS2) enzyme, a potential pharmacological target against SARS-CoV-2, involved in the spread and pathogenesis of the virus. Since 3D structure is not available for this protein, the present study aims at homology modelling and validation of TMPRSS2 using Swiss-model server. Validation of the modelled TMPRSS2 using various online tools confirmed model accuracy, topology and stereochemical plausibility. The catalytic triad consisting of Serine-441, Histidine-296 and Aspartic acid-345 was identified as active binding site of TMPRSS2 using existing ligands. Molecular docking studies of various drugs and phytochemicals against the modelled TMPRSS2 were performed using camostat as a standard drug. The results revealed eight potential drug candidates, namely nafamostat, meloxicam, ganodermanontriol, columbin, myricetin, proanthocyanidin A2, jatrorrhizine and baicalein, which were further studied for ADME/T properties. In conclusion, the study unravelled eight high affinity binding compounds, which may serve as potent antagonists against TMPRSS2 to impact COVID-19 drug therapy.
Insights
This study identified eight potential drug candidates that bind to the TMPRSS2 enzyme, a key target for inhibiting SARS-CoV-2. These compounds show promise for developing new COVID-19 therapies.
Area of Science:
- Computational drug discovery
- Virology
- Biochemistry
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates novel therapeutic strategies due to a lack of effective treatments.
- In silico approaches offer a time-efficient alternative to experimental drug discovery for identifying antiviral agents.
- Transmembrane protease serine 2 (TMPRSS2) is a critical viral entry factor and a promising pharmacological target.
Purpose of the Study:
- To perform homology modeling and validation of the TMPRSS2 enzyme structure.
- To identify potential drug candidates that can inhibit TMPRSS2 activity.
- To evaluate the drug-likeness of identified compounds.
Main Methods:
- Homology modeling of TMPRSS2 using the Swiss-model server.
- Validation of the 3D model using various online tools.
- Molecular docking of drugs and phytochemicals against the modeled TMPRSS2 active site.
- ADME/T property prediction for top-ranked compounds.
Main Results:
- A validated 3D model of TMPRSS2 was generated.
- Eight compounds, including nafamostat, meloxicam, and baicalein, showed high affinity binding to the TMPRSS2 active site.
- These compounds exhibited favorable predicted ADME/T properties.
Conclusions:
- The study successfully identified eight potential high-affinity binding compounds against TMPRSS2.
- These compounds represent promising candidates for further development as COVID-19 therapeutics.
- In silico methods provide an effective strategy for rapid identification of drug leads against viral targets.
