Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

  • ACS Pharmacol Transl Sci. 2020 Oct 14;3(6):1278-1292. doi: 10.1021/acsptsci.0c00131.
Giovanni Bocci  1 ,  Steven B Bradfute  2 ,  Chunyan Ye  2 ,  Matthew J Garcia  3 ,  Jyothi Parvathareddy  4 ,  Walter Reichard  4 ,  Surekha Surendranathan  4 ,  Shruti Bansal  4 ,  Cristian G Bologa  1 ,  Douglas J Perkins  2 ,  Colleen B Jonsson  4 ,  Larry A Sklar  3 ,  Tudor I Oprea  1  5  6
Affiliations
  • 1. Translational Informatics Division, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States.
  • 2. Center for Global Health, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States.
  • 3. UNM Center for Molecular Discovery, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States.
  • 4. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States.
  • 5. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 413 90, Sweden.
  • 6. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
PMID: 33330842 DOI: 10.1021/acsptsci.0c00131
Abstract

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 pK a 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.

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