Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

“…Virtual screening techniques have been adopted to identify compounds, often among sets of known drugs or natural products to target SARS-CoV-2 or host proteins [38][39][40][41][42]. Ligand-based approaches, docking and molecular dynamics (MD) simulation have been used per se or in combination with in vitro assays [43,44].…”

Exploring Drugs and Vaccines Associated with Altered Risks and Severity of COVID-19: A UK Biobank Cohort Study of All ATC Level-4 Drug Categories Reveals Repositioning Opportunities

“…For instance, one widely used methodology is the network-based approach, which can integrate different data sources, including omics data and drug–protein–disease interaction networks [ 16 , 19 , 20 , 21 ]. Another methodology is the structure-based approach, which enables a large number of compounds to be screened for their ability to bind to known or predicted molecular targets for COVID-19 treatment [ 16 , 22 , 23 , 24 , 25 ]. These methodologies are promising but may have their limitations.…”

Evaluation of Inhibitory Activity In Silico of In-House Thiomorpholine Compounds between the ACE2 Receptor and S1 Subunit of SARS-CoV-2 Spike

“…Because of this, many groups of scientists around the world are currently working hard to find, through different methodologies, an arsenal of effective drugs against the virus. One such strategy is drug repositioning, which consists of testing already-approved drugs used for other diseases against SARS-CoV-2 [27][28][29][30]. In addition to this, various research groups have used their own molecules synthesized in their laboratories and have proposed them as possible candidates against COVID-19 [31,32].…”