Buchumschlag

Repurposing FDA-Approved Drugs as Hendra Virus RNA-Dependent RNA Polymerase Inhibitors: A Comprehensive Computational Drug Discovery Approach

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Veröffentlicht in:Viruses vol. 17, no. 12 (2025), p. 1613-1633
1. Verfasser: Lalu, Anjana C
Weitere Verfasser: Kundil, Varun Thachan, Joseph Bristow Ben, Dev Radul R., Amritha, Thaikkad, Subair Suhail, Raju Rajesh, Abhithaj, Jayanandan
Veröffentlicht:
MDPI AG
Schlagworte:
Food & Drug Administration > FDA
Australia
Physiology
RNA polymerase
RNA-directed RNA polymerase
Toxicity
Binding sites
Hydrogen
Drug development
Computer applications
DNA-directed RNA polymerase
Antiviral agents
Bioavailability
Proteins
Crystal structure
Simulation
Fatalities
RNA viruses
Pharmacokinetics
FDA approval
Pamidronic acid
Conserved sequence
Bisphosphonates
Ligands
Viruses
Homology
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Abstract:Hendra virus (HeV) is a highly pathogenic zoonotic paramyxovirus that poses a serious threat to human and equine health, yet no approved antivirals or vaccines currently exist. RNA-dependent RNA polymerase (RdRp) of Hendra virus represents a critical and attractive target for antiviral drug development, given its essential role in both viral genome replication and mRNA transcription. Due to the lack of a human homolog, it is more druggable and less likely to cause host toxicity. Its sequence conservation among related paramyxoviruses further highlights its potential for the development of broad-spectrum inhibitors. This study offers the first comprehensive computational analysis of the Hendra virus RdRp, potentially promising FDA-approved drugs as possible inhibitors. A homology model of RdRp was generated in the absence of experimental three-dimensional (3D) structure, followed by virtual screening and molecular dynamics (MD) simulations to evaluate the drug binding and stability. Based on the highest energy, four FDA-approved drugs selected were menadiol diphosphate (−49.88 kcal/mol), masoprocol (−39.69 kcal/mol), pamidronic acid (−34.29 kcal/mol), and dinoprostone (−46.90 kcal/mol). Furthermore, these compounds exhibited significant interactions with the catalytic GDNE motif. With strong conformational stability and pharmacokinetic profile, masoprocol and menadiol diphosphate showed the most stable and energetically favorable interactions within the RdRp active site. These findings suggest their potential as repurposed therapeutic candidates against Hendra virus infection and they provide a structural basis for the development of broad-spectrum paramyxovirus inhibitors, justifying additional experimental confirmation.
ISSN:1999-4915
DOI:10.3390/v17121613
Quelle:Health & Medical Collection