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Editorial
. 2020 Jul;25(7):1126-1128.
doi: 10.1016/j.drudis.2020.05.002. Epub 2020 May 13.

Shotgun drug repurposing biotechnology to tackle epidemics and pandemics

William Mangione  1 , Zackary Falls  1 , Thomas Melendy  2 , Gaurav Chopra  3 , Ram Samudrala  4
Affiliations
Editorial

Shotgun drug repurposing biotechnology to tackle epidemics and pandemics

William Mangione et al. Drug Discov Today. 2020 Jul.
No abstract available

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Figures

Figure 1
Figure 1
A selection of putative drug candidates of preclinical and clinical interest against SARS-CoV-2 and COVID-19 generated by the CANDO shotgun repurposing platform (left). The orange arrows in decreasing thickness indicate the interaction score (1st, 5th, or 10th percentile) between the drug and predicted protein target. In the case of prodrug remdesivir, conversion to its active form diminishes its predicted interaction with the protease and greatly strengthens it with the RdRP: The top predicted poses of the active form of remdesivir docked to the solved and template-based model structures of the RdRP (right) from both SARS-CoV and SARS-CoV-2 using CANDOCK indicate binding directly into the catalytic site (colored blue). The site consists of two adjacent aspartic acid residues, indicating that remdesivir disrupts RdRP function when it binds and is potentially effective against at least two different coronaviruses. Other interesting predictions from our March 16, 2020 round (http://protinfo.compbio.buffalo.edu/cando/results/covid19/) include ACE inhibitors at rank 25-30, remdesivir at rank 54, and darunavir and other HIV protease inhibitors at rank 55-60. A separate pipeline within CANDO based on drug-drug similarity to known SARS-CoV actives identified chloroquine and other antimalarials at rank 36-41, which may be effective via a host-based mechanism since no viral proteins are predicted to be strongly targeted. All of the highlighted candidates have been shown or are believed to have activity against SARS-CoV-2 and/or are undergoing clinical trials to demonstrate efficacy . Additionally, the drugs at rank 1 and 14 (omacetaxine mepesuccinate and mycophenolate mofetil, not shown) were previously identified in experimental assays to be potent inhibitors of coronaviruses , . Therefore, the other higher ranked drugs in our lists are also worth evaluating, with the potential payoff of choice, greater efficacy, and reduced cost for compassionate off-label use and/or in clinical trials. Shotgun repurposing platforms such as CANDO not only generates short lists of therapeutic candidates rapidly but may also provide mechanistic atomic level detail of relevant interactions between targets and repurposable drugs identified by us or by any other means (including serendipity and analysis of medical records).
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