Molecular Fragment Screening Identifies Potential SARS-CoV-2 Inhibitors

04/14/2021

Overview of inhibitor fragment discovery for SARS-CoV-2. X-ray macromolecular crystallography and computational molecular docking were used to screen three libraries for unique fragments capable of binding to, and potentially inhibiting, the SARS-CoV-2 macrodomain (Mac1). Of the 20 million fragments screened, 234 were validated by isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and an HTRF-based ADPr-peptide displacement assay. [Reprinted under a Creative Commons Attribution 4.0 International (CC BY 4.0) license from Schuller M. et al.2021. "Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking." Science Advances 7(16), eabf8711. DOI:10.1126/sciadv.abf8711.]

Research published in Science Advances provides a template for developing direct-acting antiviral drugs, with novel modes of action, to combat COVID-19 by suppressing the SARS-CoV-2 viral infection.

Surface representation of a SARS-CoV-2 macrodomain (Nsp3 Mac1) bound to the host signaling molecule ADPr (cyan), which inhibits the host immune response. [Credit: M. Schuller, et al. 2021. DOI:10.1126/sciadv.abf8711]

The study focused on the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response. This part of the virus’s machinery, known as Mac1, is essential for its reproduction; previous studies have shown that viruses that lack it cannot replicate in human cells, suggesting that blocking it with a drug would have the same effect.

A large-scale crystallographic screening effort combined with computational docking identified 234 new molecules capable of targeting the active site of Mac1. These fragment structures provide starting points for developing potent SARS-CoV-2 Mac1 inhibitors.

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References

M. Schuller, G. J. Correy, S. Gahbauer, D. Fearon, T. Wu, R. E. Díaz, et al. “Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.” Science Advances (2021) Vol. 7, Issue 16, Pages eabf8711. [DOI: 10.1126/sciadv.abf8711]