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Virtual and in Vitr...
Virtual and in Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19
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Bocci, G. (author)
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Bradfute, S. B. (author)
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Ye, C. (author)
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Garcia, M. J. (author)
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Parvathareddy, J. (author)
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Reichard, W. (author)
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Surendranathan, S. (author)
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Bansal, S. (author)
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Bologa, C. G. (author)
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Perkins, D. J. (author)
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Jonsson, C. B. (author)
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Sklar, L. A. (author)
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- Oprea, Tudor I (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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(creator_code:org_t)
- 2020-10-14
- 2020
- English.
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In: ACS Pharmacology and Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 3:6, s. 1278-1292
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Abstract
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- The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite (N-monodesethyl amodiaquine) is also discussed. In trying to understand the "hydroxychloroquine"mechanism of action, both pKa and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics. © 2020 American Chemical Society. All rights reserved.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Keyword
- amodiaquine
- COVID-19
- drug repositioning
- drug repurposing
- nebivolol
- virtual screening
- zuclopenthixol
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Bocci, G.
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Bradfute, S. B.
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Ye, C.
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Garcia, M. J.
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Parvathareddy, J ...
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Reichard, W.
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show more...
-
Surendranathan, ...
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Bansal, S.
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Bologa, C. G.
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Perkins, D. J.
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Jonsson, C. B.
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Sklar, L. A.
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Oprea, Tudor I
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
- Articles in the publication
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ACS Pharmacology ...
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University of Gothenburg