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

Authors

• Giovanni Bocci, Translational Informatics Division, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
• Steven B. Bradfute, Center for Global Health, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
• Chunyan Ye, Center for Global Health, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
• Matthew J. Garcia, UNM Center for Molecular Discovery, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
• Jyothi Parvathareddy, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States
• Walter Reichard, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States
• Surekha Surendranathan, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States
• Shruti Bansal, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States
• Cristian G. Bologa, Translational Informatics Division, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States.
• Douglas J. Perkins, enter for Global Health, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States
• Colleen B. Jonsson, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 3816, United States
• Tudor I. Oprea, Translational Informatics Division, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United StatesDepartment of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, 413 90, SwedenNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark
• Larry A. Sklar, UNM Center for Molecular Discovery, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, United States

Document Type

Article

Publication Date

12-11-2020

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.

Recommended Citation

Bocci G, Bradfute SB, Ye C, Garcia MJ, Parvathareddy J, Reichard W, Surendranathan S, Bansal S, Bologa CG, Perkins DJ, Jonsson CB, Sklar LA, Oprea TI. 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. PMID: 33330842; PMCID: PMC7571299.