A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study.
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ABSTRACT:
SUBMITTER: Novak J
PROVIDER: S-EPMC8743077 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wreaked havoc all over the world. Although vaccines for the disease have recently become available and started to be administered to the population in various countries, there is still a strong and urgent need for treatments to cure COVID-19. One of the safest and fastest strategies is represented by drug repurposing (DRPx). In this study, thirty compounds with known safety profiles were identified from a chemical library of Phase II-and-up compounds through a combination of SOM Biotech's Artificial Intelligence (AI) technology, SOMAIPRO, and in silico docking calculations with third-party software. The selected compounds were then tested in vitro for inhibitory activity against SARS-CoV-2 main protease (3CLpro or Mpro). Of the thirty compounds, three (cynarine, eravacycline, and prexasertib) displayed strong inhibitory activity against SARS-CoV-2 3CLpro. VeroE6 cells infected with SARS-CoV-2 were used to find the cell protection capability of each candidate. Among the three compounds, only eravacycline showed potential antiviral activities with no significant cytotoxicity. A further study is planned for pre-clinical trials.
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Project description:The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in Chinese city of Wuhan has caused around 906,092 deaths and 28,040,853 confirmed cases worldwide (https://covid19.who.int/, 11 September 2020). In a life-threatening situation, where there is no specific and licensed anti-COVID-19 vaccine or medicine available; the repurposed drug might act as a silver bullet. Currently, more than 211 vaccines, 80 antibodies, 31 antiviral drugs, 35 cell-based, 6 RNA-based and 131 other drugs are in clinical trials. It is therefore utter need of the hour to develop an effective drug that can be used for the treatment of COVID-19 before a vaccine can be developed. One of the best-characterized and attractive drug targets among coronaviruses is the main protease (3CLpro). Therefore, the current study focuses on the molecular docking analysis of TAT-peptide47-57 (GRKKRRQRRRP)-conjugated repurposed drugs (i.e., lopinavir, ritonavir, favipiravir, and hydroxychloroquine) with SARS-CoV-2 main protease (3CLpro) to discover potential efficacy of TAT-peptide (TP) - conjugated repurposing drugs against SARS-CoV-2. The molecular docking results validated that TP-conjugated ritonavir, lopinavir, favipiravir, and hydroxychloroquine have superior and significantly enhanced interactions with the target SARS-CoV-2 main protease. In-silico approach employed in this study suggests that the combination of the drug with TP is an excelling alternative to develop a novel drug for the treatment of SARS-CoV-2 infected patients. The development of TP based delivery of repurposing drugs might be an excellent approach to enhance the efficacy of the existing drugs for the treatment of COVID-19. The predictions from the results obtained provide invaluable information that can be utilized for the choice of candidate drugs for in vitro, in vivo and clinical trials. The outcome from this work prove crucial for exploring and developing novel cost-effective and biocompatible TP conjugated anti-SARS-CoV-2 therapeutic agents in immediate future.
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Project description:The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.Communicated by Ramaswamy H. Sarma.
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Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.
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Project description:Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world's acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.
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