Simulation of Molecular Dynamics of SARS-CoV-2 S-Protein in the Presence of Multiple Arbidol Molecules: Interactions and Binding Mode Insights

Abstract

In this work, we evaluated the antiviral activity of Arbidol (Umifenovir) against SARS-CoV-2 using a pseudoviral system with the glycoprotein S of the SARS-CoV-2 virus on its surface. In order to search for binding sites to protein S of the virus, we described alternative binding sites of Arbidol in RBD and in the ACE-2-RBD complex. As a result of our molecular dynamics simulations combined with molecular docking data, we note the following fact: wherever the molecules of Arbidol bind, the interaction of the latter affects the structural flexibility of the protein. This interaction may result both in a change in the shape of the domain–enzyme binding interface and simply in a change in the structural flexibility of the domain, which can subsequently affect its affinity to the enzyme. In addition, we examined the possibility of Arbidol binding in the stem part of the surface protein. The possibility of Arbidol binding in different parts of the protein is not excluded. This may explain the antiviral activity of Arbidol. Our results could be useful for researchers searching for effective SARS-CoV-2 virus inhibitors targeting the viral entry stage.

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“…This greatly complicates the search for a binding site for entry inhibitors. The possible binding sites were considered: the binding site of Arbidol [ 41 , 42 ] located in the region of heptad repeats (HR1), the region of the likely binding of UA-30 [ 43 ] and nelfinavir [ 44 ], located at the boundary of the two subunits of protein, and the NTD cavity [ 34 ]. Using the Phase plugin [ 45 ] by Schrodinger Suite software, the pharmacophoric profile of binding sites was described.…”

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“…A possible binding site was selected in accordance with early published modelling results shown in [35,36]. Compound 21 can be located in the hydrophobic cleft, located between the α-helices of protomers.…”

“…Since it is known that pseudoviruses containing the SARS-CoV-2 S protein on their surface either do not infect the original HEK293T cells at all, or infect them with low efficiency [34], we used HEK293T-ACE2 (s) stably exhibiting angiotensin-converting enzyme 2 (ACE2) on its surface, since the SARS-CoV-2 S protein is known to interact with ACE2 as its target [35]. Additionally, HEK293T-hACE2-TMPRSS2 (t) cells obtained transiently and containing both hACE2 and TMPRSS2 on their surface were used, since it was shown that the viral entry requires priming of the S-protein by cellular proteases, such as the TMPRSS2 serine protease, which ensures fusion of viral and cell membranes [36]. According to the results obtained, the best infectivity of pseudoviral particles is observed for HEK293T-hACE2-TMPRSS2 (t) cells, while on HEK293T-ACE2 (s) cells, our SARS-CoV-2 pseudoviruses had a ten-fold lower infectivity and were almost non-contagious in HEK293T cells (Figure 2).…”

“…The presence of similar heptad repeats in HAs and S-protein suggests similar hydrophobic cavities (hydrophobic amino acids are shown by green spheres in Figure 6B) in the space between the spirals of the stem part of the protein. It is also assumed that Arbidol, which exhibits moderate antiviral activity against SARS-CoV-2 in in vitro tests [59,60], binds exactly in the stem portion of the S-protein domain [35,36] (Figure 6B). (B)-Surface viral proteins hemagglutinin (HA) of influenza virus and glycoprotein (S-protein) SARS-CoV-2.…”

“…Analysis of the results of molecular dynamics simulations allows us to specify a possible binding site for potential S-protein inhibitors of SARS-CoV-2. The starting location of compound 21 was created based on the results of molecular dynamics of the S-protein system-3 Arbidol molecules located in the region of central and heptad repeats between the two protomers of the protein [35,36]. Just as in the case of Arbidol, there are three potential inhibitor molecules per S-protein of SARS-CoV-2.…”