Hotspot residues and resistance mutations in the nirmatrelvir-binding site of SARS-CoV-2 main protease: Design, identification, and correlation with globally circulating viral genomes

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

“…Another recent publication used combination of in silico mutational scanning combined with in-vitro testing to identify mutants N142L, E166M, Q189E, Q189I, and Q192T where nirmatrelvir showed reduced potency ( 26 ). Similar residues were also identified by in-silico molecular dynamics and high-throughput protein design approaches ( 27 , 28 ).…”

The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms

“…However, a recent computational high-throughput protein design study identified F140I and G143D as potential mutations conferring resistance to nirmatrelvir. 66…”

Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

“…It is clear, nevertheless, that we have only studied a limited number of the mutational pathways that SARS-CoV-2 took to evade nirmatrelvir. Furthermore, many of the mutations revealed by our study are without a straightforward structural explanation at this time, and indeed, while other in vitro or in silico studies have identified residues such as E166 to be of importance, they have missed these other residues that are distant from the substrate binding site [39][40][41] . It should also be mentioned that our studies were conducted with the ancestral WA1 strain, and the currently circulating Omicron variants, all of which except for BA.…”