Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase

Abstract

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments.

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

“…Other reports suggest that MM/PBSA binding energies were better for ranking than docking scoring functions [ 70 ], while others have shown no significant difference [ 71 ], with both being less effective than MD alchemical methods. Our prior studies on repurposing drugs active against SARS-CoV-2 enzyme targets also established a strong correlation between MM/PBSA energies and those calculated from a thermodynamic cycle [ 9 , 11 ]. A critical review of simulation methods to study SARS-CoV-2 and repurpose drugs has been published recently by Muratov et al [ 72 ].…”

“…Literature analysis of the modes of action of these classes, and published work on their efficacy against SARS-CoV-2, provide mechanistic information and validate our computational screening approach as useful for identifying repurposing candidates. This approach was adopted in our published repurposing studies on the SARS-CoV-2 main protease (M pro ), helicase, and RNA-dependent RNA polymerase [ 8 , 9 , 11 ].…”

“…We have reported computational studies on S protein and ACE2 to elucidate the origins of SARS-CoV-2 and identify repurposed drugs inhibiting its main protease, RNA-dependent RNA polymerase, and helicase [ 8 , 9 , 10 , 11 ]. Here, we used the S protein FABP structure to identify repurposing candidates as SARS-CoV-2 treatments.…”

Exploring the Potency of Antiviral Marine Alkaloids Against Japanese encephalitis and Ebola virus: A Computational-Based Assessment for Drug Repurposing Applications

“…After the SARS-CoV-2 pandemic, the concept of repurposing drug discovery was widely accepted as a cost-effective and resource-saving strategy to counter the health emergency. Natural products, in addition to drugs, are gaining popularity for use in repurposing drug discovery platforms (Swain et al, 2021;Musarra-Pizzo et al, 2021;Piplani et al, 2022;Sahoo et al, 2022b). Surprisingly, a large number of marine alkaloids have been approved, with more in clinical trials.…”

Recent Progress in Research on COVID-19 Pathophysiology: Biomarkers, Repurposed Drugs, Viral Invasiveness, SARS-CoV-2 Genetic Diversity, the Crystal Structure of Viral Proteins, and the Molecular and Cellular Outcomes of COVID-19

“…From the beginning of the COVID-19 pandemic, the repurposing of existing drugs was considered the most rapid way to identify potential new treatments for SARS-CoV-2. Sakshi Piplani and colleagues [9] applied a virtual screening approach to find repurposed drugs against the SARS-CoV-2 helicase (non-structural protein nsp13). Their top hits were not only the expected antivirals, but also antihistamines and antipsychotics.…”