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Click triazole as a linker for drug repurposing against SARs-CoV-2: A greener approach in race to find COVID-19 therapeutic

ABSTRACT: WHO holding the hands of the scientific commune and trying to repurpose the drugs against the SARS-CoV-2. The robust scientific data has illustrated the probable mechanistic path of SARS-CoV-2 entry and action in damaging the cells. Which further has demonstrated Hydroxychloroquine (HCQ; antimalarial drug) as promising drug therapeutic; apart from certain setbacks to be an excellent agent in treating COVID-19. In the present study, we have explored the derivatives of HCQ, conjugated with bioactive agents by the virtue of sustainably modified clicked triazole approach as potential Mpro enzyme inhibitors. In results, we found the chloroquinetrithaizone has strong binding affinity for the Mpro enzyme of SARS CoV-2. We also found the stable binding of CQ-TrOne conjugate with Mpro by MD simulation studies through RMSD, RMSF and Rg calculations. Moreover, in conjunction with critical reaction coordinate outcomes, binding MMGB/PB energy profile depicted the efficient binding affinity towards Mpro. Also, DFT analyses illustrated the stability of the repurposed drug under study. These significant outcomes have shown high potency of compounds and can be further assessed through in vitro and in vivo assays to develop the effective drug against COVID-19. Graphical abstract Image 1

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC7874918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A SARS-CoV-2 (COVID-19) biological network to find targets for drug repurposing.

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Project description:The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.

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Project description: Not available

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Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19.

Project description:SARS-CoV-2 is causative agent of COVID-19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID-19. Nonstructural protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID-19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia, respectively, were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250, and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be -141 ± 11 and -136 ± 16 kJ/mol, respectively. The IC50 were predicted to be 9.2 µM and 30 µM for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8Å2 by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19. Communicated by Ramaswamy H. Sarma.

| S-EPMC7298882 | biostudies-literature

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