In Silico Drug Repurposing of FDA-Approved Drugs Highlighting Promacta as a Potential Inhibitor of H7N9 Influenza Virus

Molecules. 2022 Jul 15;27(14):4515. doi: 10.3390/molecules27144515.

Abstract

Influenza virus infections continue to be a significant and recurrent public health problem. Although vaccine efficacy varies, regular immunisation is the most effective method for suppressing the influenza virus. Antiviral drugs are available for influenza, although two of the four FDA-approved antiviral treatments have resulted in significant drug resistance. Therefore, new treatments are being sought to reduce the burden of flu-related illness. The time-consuming development of treatments for new and re-emerging diseases such as influenza and the high failure rate are increasing concerns. In this context, we used an in silico-based drug repurposing method to repurpose FDA-approved drugs as potential therapies against the H7N9 virus. To find potential inhibitors, a total of 2568 drugs were screened. Promacta, tucatinib, and lurasidone were identified as promising hits in the DrugBank database. According to the calculations of MM-GBSA, tucatinib (-54.11 kcal/mol) and Promacta (-56.20 kcal/mol) occupied the active site of neuraminidase with a higher binding affinity than the standard drug peramivir (-49.09 kcal/mol). Molecular dynamics (MD) simulation studies showed that the C-α atom backbones of the complexes of tucatinib and Promacta neuraminidase were stable throughout the simulation period. According to ADME analysis, the hit compounds have a high gastrointestinal absorption (GI) and do not exhibit properties that allow them to cross the blood-brain barrier (BBB). According to the in silico toxicity prediction, Promacta is not cardiotoxic, while lurasidone and tucatinib show only weak inhibition. Therefore, we propose to test these compounds experimentally against the influenza H7N9 virus. The investigation and validation of these potential H7N9 inhibitors would be beneficial in order to bring these compounds into clinical settings.

Keywords: FDA-approved drugs; H7N9; drug repurposing; in silico method; influenza A virus; molecular dynamics simulations; virtual screening.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Benzoates
  • Drug Repositioning
  • Humans
  • Hydrazines
  • Influenza A Virus, H7N9 Subtype*
  • Influenza, Human* / drug therapy
  • Lurasidone Hydrochloride / pharmacology
  • Lurasidone Hydrochloride / therapeutic use
  • Neuraminidase / chemistry
  • Pyrazoles

Substances

  • Antiviral Agents
  • Benzoates
  • Hydrazines
  • Pyrazoles
  • Neuraminidase
  • Lurasidone Hydrochloride
  • eltrombopag

Grants and funding

This research received no external funding.