Piece of the puzzle: Remdesivir disassembles the multimeric SARS-CoV-2 RNA-dependent RNA polymerase complex.

The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P). In this study, we theorize, using computational simulations, novel mechanisms that may underlie the binding of Rem-P to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8). More so, Rem-P interacted with a relatively higher affinity (ΔG) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P while its flexible P tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.