The
COVID-19 pandemic has spread rapidly and poses 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 anti-
influenza drug,
arbidol, for the clinical treatment of
COVID-19. Reports indicate that
arbidol could neutralize SARS-CoV-2. Monotherapy with
arbidol is superior to
lopinavir-
ritonavir or
favipiravir for treating
COVID-19. In
SARS-CoV-2 infection,
arbidol acts by interfering with viral binding to host cells. However, the detailed mechanism by which
arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition of SARS-CoV-2 by
arbidol. 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 generates favorable interactions between them. Based on our MD simulation results, we propose that the binding of
arbidol induces structural rigidity in the viral
glycoprotein, thus restricting 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.