Predicting and designing therapeutics against the Nipah virus

PLoS Negl Trop Dis. 2019 Dec 12;13(12):e0007419. doi: 10.1371/journal.pntd.0007419. eCollection 2019 Dec.

Abstract

Despite Nipah virus outbreaks having high mortality rates (>70% in Southeast Asia), there are no licensed drugs against it. In this study, we have considered all 9 Nipah proteins as potential therapeutic targets and computationally identified 4 putative peptide inhibitors (against G, F and M proteins) and 146 small molecule inhibitors (against F, G, M, N, and P proteins). The computations include extensive homology/ab initio modeling, peptide design and small molecule docking. An important contribution of this study is the increased structural characterization of Nipah proteins by approximately 90% of what is deposited in the PDB. In addition, we have carried out molecular dynamics simulations on all the designed protein-peptide complexes and on 13 of the top shortlisted small molecule ligands to check for stability and to estimate binding strengths. Details, including atomic coordinates of all the proteins and their ligand bound complexes, can be accessed at http://cospi.iiserpune.ac.in/Nipah. Our strategy was to tackle the development of therapeutics on a proteome wide scale and the lead compounds identified could be attractive starting points for drug development. To counter the threat of drug resistance, we have analysed the sequences of the viral strains from different outbreaks, to check whether they would be sensitive to the binding of the proposed inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / isolation & purification*
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Molecular Dynamics Simulation
  • Nipah Virus / drug effects*
  • Protein Binding
  • Protein Conformation
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry

Substances

  • Antiviral Agents
  • Viral Proteins

Grants and funding

MS Madhusudhan would like to acknowledge the Wellcome Trust-DBT India alliance for a senior fellowship. Neeladri Sen and Sanjana Nair would like to acknowledge CSIR-SPMF for funding. Kaustubh Amritkar would like to acknowledge INSIPRE-SHE fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.