Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations

Abstract

The COVID-19 pandemic has spread rapidly and posed an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). China's prevention and treatment guidelines suggest the use of an antiinfluenza drug, arbidol, for the clinical treatment of COVID-19. Reports indicate that arbidol could neutralize SARS-CoV-2. Monotherapy with arbidol is found to be superior to lopinavir-ritonavir or favipiravir for treating COVID-19. In SARS-CoV-2 infection, arbidol acts by interfering with viral binding to the host cells. However, the detailed mechanism through which arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition by arbidol for SARS-CoV-2. Molecular dynamics (MD) simulation-based analyses demonstrate that arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with the RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between the RBD and ACE2 in the arbidol-bound RBD/ACE2 complex, suggesting that arbidol could generate favorable interactions between them. Based on our MD simulation results, we propose that the binding of arbidol induces structural rigidity in the viral glycoprotein, resulting in a restriction of the conformational rearrangements associated with membrane fusion and virus entry. Furthermore, key residues of the RBD and ACE2 that interact with arbidol were identified, opening the door for developing therapeutic strategies and higher-efficacy arbidol derivatives or lead drug candidates.

Cell entry by SARS-CoV-2

“…Molecular dynamics simulation analyses revealed that Arbidol may bind to both RBD and ACE2 at the contacting interface, with a higher affinity for RBD. The presence of Arbidol may impair the interactions between S and ACE2 to prevent viral entry [96]. Moreover, several fusion-inhibitory peptides have been developed with potent antiviral efficacies in vitro which bind to the HR1 domain of S2 subunit and prevent the conformational changes required for membrane fusion [97][98][99][100][101][102].…”

Accelerating COVID-19 Research Using Molecular Dynamics Simulation

“…It was proposed that the binding of Arbidol induces structural rigidity in the virus glycoprotein, resulting in restriction of the conformational rearrangements associated with membrane attachment and virus entry. 58 In a related study, MD simulations and structural analyses were carried out to highlight that Arbidol blocks the S-protein trimerization, which is crucial for host cell adhesion and hijacking. 59 A supervised MD study further explored the druggability of the SARS-CoV-2 S-protein, which showed that six FDA-approved drugs were capable of significantly blocking the RBD/ACE2 interaction.…”

COVID19-inhibitory activity of withanolides involves targeting of the host cell surface receptor ACE2: insights from computational and biochemical assays

“…All the ligands were docked at the ACE2 binding site to investigate their best binding pose and binding energy. As many studies have reported an anti-influenza drug, Umifenovir, to be effective against ACE2-Spike protein interactions and is currently being tested in clinical trial against SARS-CoV-2 (Choudhary & Silakari, 2020 ; Padhi et al., 2021 ), so we chose this drug as a positive control for the computational study. When we docked Umifenovir at ACE2 binding site, the docking score in the best binding pose was −4.31 kcal/mol and it was participating in the interaction by making hydrogen bond contacts with Lys31 and Glu35 ( Figure 2(A) ).…”