Abstract
The outbreak of the novel coronavirus severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) respiratory disease, led to a global pandemic with high morbidity and mortality. Despite frenzied efforts in therapeutic development, there are currently no effective drugs for treatment, nor are there vaccines for its prevention. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, is one of the most practical treatment options against the outbreak. In this study, we present a novel strategy for in silico molecular modeling screening for potential drugs that may interact with multiple main proteins of SARS-CoV-2. Targeting multiple viral proteins is a novel drug discovery concept in that it enables the potential drugs to act on different stages of the virus’ life cycle, thereby potentially maximizing the drug potency. We screened 2631 US Food and Drug Administration (FDA)-approved small molecules against 4 key proteins of SARS-CoV-2 that are known as attractive targets for antiviral drug development. In total, we identified 29 drugs that could actively interact with 2 or more target proteins, with 5 drugs (avapritinib, bictegravir, ziprasidone, capmatinib, and pexidartinib) being common candidates for all 4 key host proteins and 3 of them possessing the desirable molecular properties. By overlaying docked positions of drug candidates onto individual host proteins, it has been further confirmed that the binding site conformations are conserved. The drugs identified in our screening provide potential guidance for experimental confirmation, such as in vitro molecular assays and in vivo animal testing, as well as incorporation into ongoing clinical studies.
【초록키워드】 COVID-19, Treatment, coronavirus disease, Drug repurposing, SARS-CoV-2, Coronavirus disease 2019, Vaccine, Drug discovery, drugs, Viral proteins, drug, in vitro, in silico, virus, antiviral drug, binding site, Novel coronavirus, effective drugs, global pandemic, Protein, outbreak, Respiratory disease, therapeutic, Clinical studies, target, Small molecules, morbidity and mortality, small molecule, molecular, respiratory, in vivo, Molecular assay, Guidance, food, host proteins, Capmatinib, life cycle, causative agent, ziprasidone, bictegravir, pexidartinib, (avapritinib, Viral protein, drug candidates, conformation, host protein, Stage, incorporation, effort, candidate, Drug administration, target proteins, drug candidate, targeting, effective, avapritinib, conserved, screened, representing, docked, effective drug, 【제목키워드】 SARS-CoV-2, FDA approved drug, target,