Abstract
Inhibition of RNA-dependent RNA polymerase (RdRp) by nucleotide analogues with ribose modification provides a promising antiviral strategy for the treatment of SARS-CoV-2. Previous works have shown that remdesivir carrying 1′-substitution can act as a “delayed chain terminator”, while nucleotide analogues with 2′-methyl group substitution could immediately terminate the chain extension. However, how the inhibition can be established by the 3′-ribose modification as well as other 2′-ribose modifications is not fully understood. Herein, we have evaluated the potential of several adenosine analogues with 2′- and/or 3′-modifications as obligate chain terminators by comprehensive structural analysis based on extensive molecular dynamics simulations. Our results suggest that 2′-modification couples with the protein environment to affect the structural stability, while 3′-hydrogen substitution inherently exerts “immediate termination” without compromising the structural stability in the active site. Our study provides an alternative promising modification scheme to orientate the further optimization of obligate terminators for SARS-CoV-2 RdRp.