1. Structure-Based Discovery of Inhibitors of the SARS-CoV‑2 Nsp14 N7-Methyltransferase
- Author
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Singh, Isha, Li, Fengling, Fink, Elissa A, Chau, Irene, Li, Alice, Rodriguez-Hernández, Annía, Glenn, Isabella, Zapatero-Belinchón, Francisco J, Rodriguez, M Luis, Devkota, Kanchan, Deng, Zhijie, White, Kris, Wan, Xiaobo, Tolmachova, Nataliya A, Moroz, Yurii S, Kaniskan, H Ümit, Ott, Melanie, García-Sastre, Adolfo, Jin, Jian, Fujimori, Danica Galonić, Irwin, John J, Vedadi, Masoud, and Shoichet, Brian K
- Subjects
Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Emerging Infectious Diseases ,Infectious Diseases ,Humans ,Methyltransferases ,SARS-CoV-2 ,Viral Nonstructural Proteins ,COVID-19 ,RNA ,Viral ,Exoribonucleases ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme's SAM site, leading to three inhibitors with IC50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.
- Published
- 2023