Systematic Down-Selection of Repurposed Drug Candidates for COVID-19

Abstract

SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

Molecular Docking and Dynamics Identifies Potential Repurposed Drug Candidates for COVID-19 Studies

“…Jain et al [18] have developed the open access, user-friendly 'CoviRx' platform to display each of the 7,817 drugs along with physical and chemical properties, original indication, available data from multiple assays, COVID-19 clinical trials, any red flags such as pregnancy concerns, contraindications, etc. and drugs that are similar to the query on the basis of the Tanimoto coefficient [20].…”

“…and drugs that are similar to the query on the basis of the Tanimoto coefficient [20]. This work made use of CoviRx.org along with the pharmacological down-selection methodology described by MacRaild et al [18] involving a combination of 11 filters such as approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. In addition, the pregnancy and pan-assay interference compounds (PAINS) categories were included to rule out drugs unsafe for pregnant women and those likely to produce false positive results.…”

“…This approach looks for new uses for approved or investigational drugs that are outside the scope of the original medical indication, and can dramatically shrink the costs and timeline involved. However, a major challenge is that there are 7,817 candidates in Compounds Australia open drug collection, so we recently developed a database to down-select the top candidates in a systematic manner [17,18]. To validate our approach experimentally, 12 of the top 214 drugs, along with the current standards of care (remdesivir, molnupiravir and nirmatrelvir/ritonavir), were recently subjected to in vitro evaluation of anti-viral efficacy against SARS-CoV-2 Delta and Omicron variants of concern [19].…”

Use of Stem Cell-Derived Cardiomyocyte and Nasal Epithelium Models to Establish a Multi-Tissue Model Platform to Validate Repurposed Drugs Against SARS-CoV-2 Infection

“…We have recently employed an in silico approach to down-select nine approved drugs (plus three anti-SARS-CoV-2 control drugs) for assessment using a commercially-sourced ALI model of the human airway epithelium [11][12][13]. Five drugs that showed promise were further evaluated against both Delta and Omicron variants of concern (VOC), with fluvoxamine exhibiting anti-SARS-CoV-2 activity, albeit at concentrations higher than can be achieved in patients [13].…”

A Quantum Chemical Study on the Anti-SARS-CoV-2 Activity of TMPRSS2 Inhibitors

“…Numerous COVID-19 treatments have been studied, resulting in the successful development of COVID-19 vaccines and anti-SARS-CoV-2 agents 4,5 that are gradually returning our lives to pre-pandemic conditions 6 . Meanwhile, many studies have reported effective COVID-19 treatment methods at the basic research level 7,8 , that are expected to be crucial in preparing for unknown viral diseases. SARS-CoV-2 is transmitted by the binding of a spike protein (S protein) in the envelope to the angiotensin-converting enzyme 2 (ACE2) receptor on the human cell membrane 9,10 .…”