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Updated: Aug 20, 2025
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Discovering new potential inhibitors to SARS-CoV-2 RNA dependent RNA polymerase (RdRp) using high throughput virtual
Dylan Brunt1, Phillip M Lakernick1, Chun Wu2
1College of Science and Mathematics, Rowan University, Glassboro, NJ, 08028, USA.
Abstract:
RNA dependent RNA polymerase (RdRp), is an essential in the RNA replication within the life cycle of the severely acute respiratory coronavirus-2 (SARS-CoV-2), causing the deadly respiratory induced sickness COVID-19. Remdesivir is a prodrug that has seen some success in inhibiting this enzyme, however there is still the pressing need for effective alternatives. In this study, we present the discovery of four non-nucleoside small molecules that bind favorably to SARS-CoV-2 RdRp over the active form of the popular drug remdesivir (RTP) and adenosine triphosphate (ATP) by utilizing high-throughput virtual screening (HTVS) against the vast ZINC compound database coupled with extensive molecular dynamics (MD) simulations. After post-trajectory analysis, we found that the simulations of complexes containing both ATP and RTP remained stable for the duration of their trajectories. Additionally, it was revealed that the phosphate tail of RTP was stabilized by both the positive amino acid pocket and magnesium ions near the entry channel of RdRp which includes residues K551, R553, R555 and K621. It was also found that residues D623, D760, and N691 further stabilized the ribose portion of RTP with U10 on the template RNA strand forming hydrogen pairs with the adenosine motif. Using these models of RdRp, we employed them to screen the ZINC database of ~ 17 million molecules. Using docking and drug properties scoring, we narrowed down our selection to fourteen candidates. These were subjected to 200 ns simulations each underwent free energy calculations. We identified four hit compounds from the ZINC database that have similar binding poses to RTP while possessing lower overall binding free energies, with ZINC097971592 having a binding free energy two times lower than RTP.
Insights
Researchers discovered four new small molecules that effectively inhibit SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). These compounds show promise as alternatives to remdesivir for treating COVID-19 by binding more favorably to the viral enzyme.
Area of Science:
- Virology
- Drug Discovery
- Computational Chemistry
Background:
- SARS-CoV-2 replication relies on RNA-dependent RNA polymerase (RdRp).
- Remdesivir (RTP) inhibits RdRp but effective alternatives are needed for COVID-19 treatment.
Purpose of the Study:
- To discover novel non-nucleoside small molecules that inhibit SARS-CoV-2 RdRp.
- To identify compounds with superior binding affinity compared to remdesivir (RTP) and ATP.
Main Methods:
- High-throughput virtual screening (HTVS) of the ZINC database.
- Molecular dynamics (MD) simulations and binding free energy calculations.
- Analysis of molecular interactions and binding poses.
Main Results:
- Four novel small molecules were identified with favorable binding to SARS-CoV-2 RdRp.
- These compounds exhibited lower binding free energies than remdesivir (RTP).
- ZINC097971592 showed a binding free energy twice as low as RTP.
Conclusions:
- The identified compounds represent promising candidates for COVID-19 antiviral therapy.
- These non-nucleoside inhibitors offer potential alternatives to current treatments.
- Computational methods are effective for discovering novel RdRp inhibitors.
