Affiliation:
1. Hebrew SeniorLife
2. Taiwan AI Labs
3. National Taiwan University
4. Broad Institute
Abstract
Abstract
We developed a computational framework that integrates Genome-Wide Association Studies (GWAS) and post-GWAS analyses, designed to facilitate drug repurposing for COVID-19 treatment. The comprehensive approach combines transcriptomic-wide associations, polygenic priority scoring, 3D genomics, viral-host protein-protein interactions, and small-molecule docking. Through GWAS, we identified nine druggable host genes associated with COVID-19 severity and SARS-CoV-2 infection, all of which show differential expression in COVID-19 patients. These genes include IFNAR1, IFNAR2, TYK2, IL10RB, CXCR6, CCR9, and OAS1. We performed an extensive molecular docking analysis of these targets using 553 small molecules derived from five therapeutically enriched categories, namely antibacterials, antivirals, antineoplastics, immunosuppressants, and anti-inflammatories. This analysis, which comprised over 20,000 individual docking analyses, enabled the identification of several promising drug candidates. All results are available via the DockCoV2 database (https://dockcov2.org/drugs/). The computational framework ultimately identified nine potential drug candidates: Peginterferon alfa-2b, Interferon alfa-2b, Interferon beta-1b, Ruxolitinib, Dactinomycin, Rolitetracycline, Irinotecan, Vinblastine, and Oritavancin. While its current focus is on COVID-19, our proposed computational framework can be applied more broadly to assist in drug repurposing efforts for a variety of diseases. Overall, this study underscores the potential of human genetic studies and the utility of a computational framework for drug repurposing in the context of COVID-19 treatment, providing a valuable resource for researchers in this field.
Publisher
Research Square Platform LLC
Reference40 articles.
1. US.Food & Drug. Coronavirus Treatment Acceleration Program. FDA. 2021. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap
2. Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics;Talevi A;Expert Opin Drug Discov.,2020
3. Drug repurposing from the perspective of pharmaceutical companies;Cha Y;Br J Pharmacol.,2018
4. Remdesivir for the Treatment of Covid-19 - Final Report;Beigel JH;N Engl J Med.,2020
5. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19;Kalil AC;N Engl J Med,2021