Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies

Abstract

Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.

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

“…Our earlier studies predicted sertindole to be a strong binder to SARS-CoV-2 RdRp [ 6 , 7 ], and the activity of sertindole against M pro also was later reported by Vatensever et al [ 44 ].…”

“…Potential conivaptan binding to the SARS-CoV-2 nsp9 replicase was found by Chandel et al using a combination of Autodock screening followed by MD simulations [ 30 ]. Several other recent computational studies have also reported potential binding of conivaptan to various SARS-CoV-2 targets (see summary in Piplani et al) [ 6 , 7 ].…”

“…There has been extensive research into drugs that might interfere in the SARS-CoV-2 spike protein’s interaction with its cognate human receptor, angiotensin-converting enzyme 2 (ACE2). Other heavily studied targets are the viral 3CL main protease (M pro , nsp5), PL protease (PL pro , nsp3), and RNA-dependent RNA polymerase (RdRp, major protein nsp12) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. However, less attention has been paid to other potential target proteins such as the SARS-CoV-2 helicase, the focus of the current study.…”

“…The SARS-CoV-2 helicase is a critical enzyme for viral replication as it initiates the first step of the RNA cap synthesis that is essential to protect the virus from innate immune attack, stabilize it, and ensure its translation. We previously developed an in silico screening protocol that was used to identify drug repurposing candidates for SARS-CoV-2 M pro and RdRp [ 5 , 6 , 7 ]. The utility of this approach was established by the large numbers of predicted candidates that had experimentally validated activity against SARS-CoV-2 and/or the specific target proteins.…”

Non-nucleoside structured compounds with antiviral activity—past 10 years (2010–2020)

“…In the face of the COVID-19 pandemic, a huge increase of interest in RdRp was observed, as it is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. For this reason, many known RdRp inhibitors (such as described in this paragraph dasabuvir [ 114 ], pimodivir [ 115 ], radalbuvir [ 116 , 117 ] and tegobuvir [ 118 ]) have been also included in the research of an effective drug for COVID-19. Elfiky and colleagues [ 119 ] made attempts to assess the possibility of using several antiviral drugs or drug candidates (including setrobuvir and mentioned earlier galidesivir) for the treatment of SARS-CoV-2 virus infections (in silico drug-repurposing).…”