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 six 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 14000 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 a plausible mechanism for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising repurposable drug candidates that are safe, efficacious, and cost-effective for the treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx, https://www.covirx.org/) that was also developed to enable scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation

“…Therefore, the quest to identify potential molecules to treat COVID-19 and PASC is still ongoing. We developed a systematic approach to catalogue all FDA/TGA approved drugs available in the Compounds Australia collection [25]; down-select 214 likely candidates [26]; evaluate in vitro/ex vivo efficacy of the top 12 leads [14]; and screen the 214 candidates using molecular modeling techniques to identify additional leads [27]. In our latter list is present a bisphosphonate molecule called alendronate, and we came across a parallel study which observed that humans who used alendronate (and another bisphosphonate called zoledronate) had lower odds ratios (typically 0.21-0.29) of testing for SARS-CoV-2 infection, COVID-19 diagnosis and COVID-19-related hospitalization [28].…”

CoviRx: A User-Friendly Interface for Systematic Down-Selection of Repurposed Drug Candidates for COVID-19

“…Visual representation of the filters used to down-select drugs and the filters passed by each drug has been added for those who would like to investigate this further. Drugs are ranked based on activity scores calculated using the assay data as described in MacRaild et al, 2022 [10]. Another important feature of this page is the dynamic calculation and display of similar drug candidates.…”

“…It displays the output along with the number of filters passed out of the total eleven designed by the research team. This computer science paper should be read in conjunction with research by MacRaild et al, 2022 [10], which describes the pharmacological methodology for systematic down-selection of repurposed drug candidates for COVID-19. To increase collaboration with the other researchers, features have been incorporated in CoviRx that allow registered users to submit their findings on any drug candidate to the CoviRx web app.…”