Article ; Online: Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity.
Bioorganic & medicinal chemistry
2024 Volume 103, Page(s) 117577
Abstract: Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes ...
Abstract | Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity. This structure-activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage. |
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MeSH term(s) | Humans ; SARS-CoV-2 ; COVID-19 ; Peptides/pharmacology ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; Protease Inhibitors/pharmacology ; Protease Inhibitors/chemistry ; Molecular Docking Simulation ; Coronavirus 3C Proteases |
Chemical Substances | 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Peptides ; Antiviral Agents ; Protease Inhibitors ; Coronavirus 3C Proteases (EC 3.4.22.28) |
Language | English |
Publishing date | 2024-01-05 |
Publishing country | England |
Document type | Journal Article |
ZDB-ID | 1161284-8 |
ISSN | 1464-3391 ; 0968-0896 |
ISSN (online) | 1464-3391 |
ISSN | 0968-0896 |
DOI | 10.1016/j.bmc.2023.117577 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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