Biostructural Models for the Binding of Nucleoside Analogs to SARS-CoV‑2 RNA-Dependent RNA Polymerase

SARS-CoV-2
is a positive-sense RNA virus that requires an RNA-dependent
RNA polymerase (RdRp) for replication of its viral genome. Nucleoside
analogs such as Remdesivir and β-d-N4-hydroxycytidine
are antiviral candidates and may function as chain terminators or
induce viral mutations, thus impairing RdRp function. Recently disclosed
Cryo-EM structures of apo, RNA-bound, and inhibitor-bound
SARS-CoV-2 RdRp provided insight into the inhibitor-bound structure
by capturing the enzyme with its reaction product: Remdesivir covalently
bound to the RNA primer strand. To gain a structural understanding
of the binding of this and several other nucleoside analogs in the
precatalytic state, molecular models were developed that predict the
noncovalent interactions to a complex of SARS-CoV-2 RdRp, RNA, and
catalytic metal cations. MM-GBSA evaluation of these interactions
is consistent with resistance-conferring mutations and existing structure–activity
relationship (SAR) data. Therefore, this approach may yield insights
into antiviral mechanisms and guide the development of experimental
drugs for COVID-19 treatment.