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Updated: Dec 13, 2025
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening
Ashish M Kanhed1, Dushyant V Patel2, Divya M Teli3
1Shobhaben Pratapbhai Patel - School of Pharmacy and Technology Management, SVKM's NMIMS University, Vile Parle, Mumbai, 400056, India.
Abstract:
The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19.
Insights
Researchers screened drug libraries to identify inhibitors of the SARS-CoV-2 main protease (Mpro), crucial for viral replication. Several existing antiviral drugs and novel compounds showed potential for developing new COVID-19 treatments.
Area of Science:
- Virology
- Drug Discovery
- Computational Chemistry
Background:
- COVID-19, caused by SARS-CoV-2, is a global pandemic characterized by severe respiratory illness.
- Viral replication depends on structural and non-structural proteins derived from polyproteins.
- The main protease (Mpro) is essential for processing these polyproteins into functional viral components.
Purpose of the Study:
- To identify potential therapeutic agents for COVID-19 by screening drug libraries against the SARS-CoV-2 main protease (Mpro).
- To discover novel Mpro inhibitors for further drug development.
Main Methods:
- Systematic screening of FDA-approved drug libraries and the Asinex BioDesign library.
- Utilized pharmacophore and conformational precision filters within the Schrodinger Suite.
- Computational analysis to predict Mpro inhibition and identify promising molecular scaffolds.
Main Results:
- Identified three potent Mpro inhibitors from the approved drug library: ritonavir, nelfinavir, and saquinavir.
- Discovered pralmorelin, iodixanol, and iotrolan, with potential for modification into safer antiviral agents.
- Screening of the Asinex BioDesign library yielded 20 molecules with promising Mpro interactions, categorized into four main scaffold classes.
Conclusions:
- Ritonavir, nelfinavir, and saquinavir are promising candidates for COVID-19 treatment due to their Mpro inhibitory activity.
- Novel compounds from the Asinex library represent valuable starting points for developing new antiviral therapies.
- Further structural modifications and development are warranted to optimize these hits into clinically viable COVID-19 therapeutics.
