Open AccessVirtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19
Author(s) -
Giovanni Bocci,
Steven B. Bradfute,
Chunyan Ye,
Matthew Garcia,
Jyothi Parvathareddy,
Walter Reichard,
Surekha Surendranathan,
Shruti Bansal,
Cristian Bologa,
Douglas J Perkins,
Colleen B. Jonsson,
Larry A. Sklar,
Tudor I. Oprea
Publication year - 2020
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.0c00131
Subject(s) - amodiaquine , hydroxychloroquine , medicine , drug repositioning , pharmacology , drug , polypharmacy , clinical trial , covid-19 , immunology , malaria , chloroquine , disease , infectious disease (medical specialty)
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 EC 50 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 p K 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.