Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase
Isha Singh, Fengling Li, Elissa A. Fink, Irene Chau, Alice Shi Ming Li, Annia Rodríguez‐Hernández, Isabella Glenn, Francisco J. Zapatero‐Belinchón, Myosotys Rodriguez, Kanchan Devkota, Zhijie Deng, Kris M. White, Xiaobo Wan, Nataliya A. Tolmachova, Yurii S. Moroz, H. Ümit Kanıskan, Mélanie Ott, Adolfo García‐Sastre, Jian Jin, Danica Galonić Fujimori, John J. Irwin, Masoud Vedadi, Brian K. Shoichet
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 IC 50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC 50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC 50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC 50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC 50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.