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ChEMBL_27 SARS-CoV-2 release



The COVID-19 pandemic has resulted in an unprecedented effort across the global scientific community. Drug discovery groups are contributing in several ways, including the screening of compounds to identify those with potential anti-SARS-CoV-2 activity. When the compounds being assayed are marketed drugs or compounds in clinical development then this may identify potential repurposing opportunities (though there are many other factors to consider including safety and PK/PD considerations; see for example https://www.medrxiv.org/content/10.1101/2020.04.16.20068379v1.full.pdf+html). The results from such compound screening can also help inform and drive our understanding of the complex interplay between virus and host at different stages of infection.

Several large-scale drug screening studies have now been described and made available as pre-prints or as peer-reviewed publications. The ChEMBL team has been following these developments with significant interest, and as a contribution to the overall COVID-19 effort we have curated the bioactivity data reported in these studies. Many of the compounds used in these studies have significant data and information already available in ChEMBL; one of our goals is to enable users to view the COVID-19 results alongside existing data and to be able to compare results from different labs (e.g. for the same compounds). We have chosen for this special release to focus on those studies which use cell-based assays to screen such well-established compounds for anti-viral activity.

Drug names were extracted from each publication and mapped to ChEMBL compound identifiers and/or chemical structures, using a combination of automated mapping and manual curation. These were incorporated into the database, along with the relevant assay/activity information, to produce the new release of ChEMBL. Full details can be found in the release notes; these datasets been incorporated as a new source (src_id = 52, SARS-CoV-2 Screening Data) and can be accessed via this link.

Here is a summary of the 8 data sets that we have curated:

CHEMBL4303084:
Jeon et al. (2020) Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Preprint DOI: 10.1101/2020.03.20.999730
In this study, 48 approved drugs were tested against SARS-CoV-2 in a Vero cell assay.

CHEMBL4303773:
Gordon et al. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Publication DOI: 10.1038/s41586-020-2286-9, PMID: 32353859
Following identification of host-viral protein interactions, a set of 75 compounds believed to be active against these proteins were tested in Vero E6 cells for activity against SARS-CoV-2.

CHEMBL4303082:
Riva et al. (2020) A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. Preprint DOI: 10.1101/2020.04.16.044016
The ReFRAME drug repurposing library of 12K compounds was tested for activity against SARS-CoV-2 in Vero E6 cells. 18 active compounds were reported.

CHEMBL4303097:
Touret et al. (2020) In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Preprint DOI: 10.1101/2020.04.03.023846
The Prestwick Chemical Library of 1520 approved drugs was screened to identify compounds active against SARS-CoV-2 in a Vero E6 cell assay.

CHEMBL4303087:
Weston et al. (2020) Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo. Preprint DOI: 10.1101/2020.03.25.008482
20 approved drugs that had previously shown activity against SARS-CoV and MERS-CoV were tested for activity against SARS-CoV-2 in a Vero E6 cell assay. A number of compounds were subsequently tested for their effect on viral fusion, and two compounds (chloroquine and chlorpromazine) were tested in a SARS-CoV infected mouse model.

CHEMBL4303101:
Ellinger et al. (2020) Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection. Preprint DOI: 10.21203/rs.3.rs-23951/v1
A large drug/candidate library (5632 compounds) was screened for activity against SARS-CoV-2 in human Caco-2 cells using an imaging assay. IC50 values were calculated for 67 compounds.

CHEMBL4303122:
Heiser et al. (2020) Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2. Preprint DOI: 10.1101/2020.04.21.054387
1670 approved drugs and reference compounds were screened for activity against SARS-CoV-2 in human renal cortical epithelial (HRCE) cells using an AI image-analysis algorithm.

CHEMBL4303121:
Si et al. (2020) Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. Preprint DOI: 10.1101/2020.04.13.039917
Effect on SARS-CoV-2 viral entry in Huh-7 cells was assessed for 7 approved drugs that have previously shown activity against other viral infections. The compounds were then assessed for antiviral activity in human lung Airway Chip at their reported Cmax. Note, this study also included influenza data, which is not currently included in this ChEMBL release.

So which drugs demonstrate activity in these assays?

There are 133 compounds with a reported IC50/EC50 better than 10uM in one or more studies and 41 compounds with an IC50/EC50 better than 1uM in one or more studies (but please bear in mind that not all studies/assays reported IC50/EC50 measurements). It is important to note that most of the studies included here also assessed the cytotoxicity of the drugs in the absence of viral infection. Some showed significant cytotoxicity in addition to their antiviral activity, at the concentrations tested, so this information should be taken into account when analysing the data. For example, of the 133 compounds with activity < 10uM, only 72 of these have a reported 'Selectivity index' > 3 (ratio of cell cytotoxicity/antiviral activity) and 44 of these are approved drugs. By switching to the Heatmap view for these compounds in ChEMBL, you can also see what other reported activities these compounds have:



The overlap in terms of which compounds are active between the different studies is fairly low. Only a handful of compounds are active in more than one study. When considering all of the different activity types measured, 14 compounds could be considered active/weakly active in more than one study and only 5 compounds were active in three or more studies: remdesivir (Ellinger, Heiser, Riva, Touret), chloroquine (Heiser, Si, Jeon), hydroxychloroquine (Gordon, Touret, Weston), mefloquine (Jeon, Ellinger, Weston) and amodiaquine (Jeon, Si, Weston).

There may be many reasons for the variation in these results, particularly as these can be very complex assays to set up and run. Assays may also differ in the cell type used (Vero-derived cell lines from African Green Monkey vs human cell lines/tissue), the SARS-CoV-2 isolates used, multiplicity of infection (MOI) tested, and the assay type/detection method.

We will continue to monitor closely COVID-19 progress as more studies are disclosed. We are very happy to receive feedback on this release of ChEMBL via chembl-help@ebi.ac.uk.

Finally, we would like to acknowledge the tremendous efforts of the researchers who have established the assays and generated the data so speedily.

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