Graphical abstract Highlights • The binding affinity towards SARS-CoV-2 nsp16 of SFG is higher than that of SAH. • Asp99 is a key binding residue for SAH and SFG via charge-charge attraction. • SFG could electrostatically interact with the 2′-OH and N3 groups of adenosine moiety of RNA substrate. • The distance between 2′-OH of RNA and –NH 3 + (at 6′ position) of SFG mimics the methyl transfer reaction. The recent ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rapidly spread across the world. To date, neither a specific antiviral drug nor a clinically effective vaccine is available. Among the 15 viral non-structural proteins (nsps), nsp16 methyltransferase has been considered as a potential target due to its crucial role in RNA cap 2′-O-methylation process, preventing the virus detection by cell innate immunity mechanisms. In the present study, molecular recognition between the two natural nucleoside analogs ( S -adenosyl- l -homocysteine (SAH) and sinefungin (SFG)) and the SARS-CoV-2 nsp16/nsp10/ m7 G ppp AC 5 was studied using all-atom molecular dynamics simulations and free energy calculations based on MM/GBSA and WaterSwap approaches. The binding affinity and the number of hot-spot residues, atomic contacts, and H-bond formations of SFG/nsp16 complex were distinctly higher than those of SAH/nsp16 system, consistent with the lower water accessibility at the enzyme active site. Notably, only SFG could electrostatically interact with the 2′-OH and N3 of RNA’s adenosine moiety, mimicking the methyl transfer reaction of S -adenosyl- l -methionine substrate. The atomistic binding mechanism obtained from this work paves the way for further optimizations and designs of more specific SARS-CoV-2 nsp16 inhibitors in the fight against COVID-19.
【저자키워드】 COVID-19, SARS-CoV-2, MD simulations, nucleoside analog, Rational drug design, Nsp16/nsp10, 【초록키워드】 coronavirus disease, Vaccine, coronavirus, pandemic, Innate immunity, binding affinity, Free energy calculation, antiviral drug, Molecular dynamics simulation, RNA, Spread, methyltransferase, virus detection, non-structural protein, mechanisms, molecular, group, inhibitor, binding, Nsps, acute respiratory syndrome, Abstract, approaches, enzyme, complex, residue, transfer, residues, binding mechanism, H-bond, effective, Cell, caused, clinically, atomic, mimicking, the SARS-CoV-2, 【제목키워드】 RNA,