The rapid global spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has created an unprecedented healthcare crisis. The treatment for the severe respiratory illness caused by this virus is primarily symptomatic at this point, although the usage of a broad antiviral drug Remdesivir has been allowed on emergency basis by the Food and Drug Administration (FDA). The ever-increasing death toll highlights an urgent need for development of specific antivirals. In this work, we have utilized docking and simulation methods to identify small molecule inhibitors of SARS-CoV-2 Membrane (M) and Envelope (E) proteins, which are essential for virus assembly and budding. A total of 70 compounds from an Indian medicinal plant source (Azadirachta indica or Neem) were virtually screened against these two proteins and further analyzed with molecular dynamics simulations, which resulted in the identification of a few common compounds with strong binding to both structural proteins. The compounds bind to biologically critical regions of M and E, indicating their potential to inhibit the functionality of these components. We hope that our computational approach may result in the identification of effective inhibitors of SARS-CoV-2 assembly.

Viroporins are oligomeric, pore forming, viral proteins that play critical roles in the life cycle of pathogenic viruses. Viroporins like HIV-1 Vpu, Alphavirus 6K, Influenza M2, HCV p7, and Picornavirus 2B, form discrete aqueous passageways which mediate ion and small molecule transport in infected cells. The alterations in host membrane structures induced by viroporins is essential for key steps in the virus life cycle like entry, replication and egress. Any disruption in viroporin functionality severely compromises viral pathogenesis. The envelope (E) protein encoded by coronaviruses is a viroporin with ion channel activity and has been shown to be crucial for the assembly and pathophysiology of coronaviruses. We used a combination of virtual database screening, molecular docking, all-atom molecular dynamics simulation and MM-PBSA analysis to test four FDA approved drugs - Tretinoin, Mefenamic Acid, Ondansetron and Artemether - as potential inhibitors of ion channels formed by SARS-CoV-2 E protein. Interaction and binding energy analysis showed that electrostatic interactions and polar solvation energy were the major driving forces for binding of the drugs, with Tretinoin being the most promising inhibitor. Tretinoin bound within the the lumen of the channel formed by E protein, which is lined by hydrophobic residues like Phe, Val and Ala, indicating its potential for blocking the channel and inhibiting the viroporin functionality of E. In control simulations, tretinoin demonstrated a lower binding energy with a known target as compared to SARS-CoV-2 E protein. This work thus highlights the possibility of exploring Tretinoin as a potential SARS-CoV-2 E protein ion channel blocker and virus assembly inhibitor, which could be an important therapeutic strategy in the treatment for coronaviruses.

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