# Accelerated discovery of cell-active SARS-CoV-2 polymerase inhibitors via molecular dynamic guided screening and optimization

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $442,542

## Abstract

Project Summary
Significance: Worldwide spread of the SARS-CoV-2 virus has resulted in over 20 million
confirmed human cases and 730,000 deaths from COVID-19, and cases continue to surge as
there is no approved vaccine or other therapeutic modality broadly available to mitigate
community spread. The virus has not only impacted human health but has also threatened
national security, economic stability, and education.
Broad, long term objectives: The research objectives described in this proposal will afford
vetted, small molecule non-nucleoside-based inhibitors of the SARS-CoV-2 viral polymerase
enzyme that will serve as lead compounds for future development and clinical evaluation
targeting COVID-19 disease.
Specific Aims/premise: The proposed aims are constructed to evaluate if potent, cell permeable,
non-nucleot/side-based inhibitors of the SARS-CoV-2 RNA polymerase can be discovered using
an integrated drug discovery pipeline. Specifically, we hypothesize that a highly efficient, dynamic
computational screening method will reveal desirable hits that will be validated in antiviral assays
to show target engagement and cellular efficacy. Further, medicinal chemistry optimization will
tune the activity and property profiles of hits to make them suitable for evaluation in our
established COVID-19 K18 hACE2 mouse models.
Research design and methods: Aim 1 will identify competitive non-nucleot/side SARS-CoV-2
RdRp inhibitors from a strategically chosen compound collection using an efficient in silico
screening approach developed and employed by Drs. Baudry and Smith. The hits will be ranked
by binding energies and selected for confirmatory activity in the Jonsson’s lab using established
cellular SARS-CoV-2 assays, along with secondary assays that validate active site inhibition of
the viral polymerase. The Golden lab will lead hit validation efforts and advance hits that meet
defined criteria to Aim 2. The latter aim will prioritize and evaluate specific scaffolds by
medicinal chemistry optimization (Golden lab), guided by the primary and secondary assays,
computational models and tiered ADME and pharmacokinetic analyses, to refine compound
activity profiles that are suitable for in vivo efficacy assessments performed in the Jonsson lab.

## Key facts

- **NIH application ID:** 10238322
- **Project number:** 1R21AI161232-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jennifer E. Golden
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,542
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238322

## Citation

> US National Institutes of Health, RePORTER application 10238322, Accelerated discovery of cell-active SARS-CoV-2 polymerase inhibitors via molecular dynamic guided screening and optimization (1R21AI161232-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10238322. Licensed CC0.

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