Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 4, Issue 5, Pages 1675-1688Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.1c00176
Keywords
COVID-19; SARS-CoV-2; virtual screening; machine learning; pharmacophore modeling
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Funding
- Intramural Research Program of the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH)
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By utilizing NCATS screening data and various models, active small molecules against SARS-CoV-2 were successfully predicted. Further investigation revealed three novel chemotypes with potential, along with the identification of potential host inhibitors.
The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytopathic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (similar to 16% of predicted hits) active compounds (efficacy > 30%, IC50 <= 15 mu M). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further investigation resulted allosteric binders to host receptor angiotensin-converting enzyme 2; these compounds were then shown pseudoparticles bearing spike protein of wild-type SARS-CoV-2, as well as South African B.1.351 and UK B.1.1.7 variants.
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