[Source: PLOS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Predicting and designing therapeutics against the Nipah virus
Neeladri Sen , Tejashree Rajaram Kanitkar , Ankit Animesh Roy , Neelesh Soni, Kaustubh Amritkar, Shreyas Supekar, Sanjana Nair, Gulzar Singh, M. S. Madhusudhan
Published: December 12, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007419
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.
Nipah virus infections have killed 72–86% of the infected individuals in Bangladesh and India. The infections are spread via bodily secretions of bats, pigs and other infected individuals. Even though, the disease was first detected in the human population in 1998, there are no approved drugs/vaccines against it. In this study, we have tried to model the 3D structures of the Nipah virus proteins. We have then used these models to design/predict inhibitory molecules that would bind them and prevent their function. We have also analysed the different strains of the virus to identify conservation patterns of amino acids in the proteins, which in turn informs us about the potential target sites for the drugs. The designed/docked compounds, as well as the protein models, are freely accessible for experimental validation and hypothesis testing.
Citation: Sen N, Kanitkar TR, Roy AA, Soni N, Amritkar K, Supekar S, et al. (2019) Predicting and designing therapeutics against the Nipah virus. PLoS Negl Trop Dis 13(12): e0007419. https://doi.org/10.1371/journal.pntd.0007419
Editor: Jeanne Salje, University of Oxford, UNITED KINGDOM
Received: April 26, 2019; Accepted: November 4, 2019; Published: December 12, 2019
Copyright: © 2019 Sen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files. The coordinates of the models of proteins and complexes with the inhibitors is publicly available at http://cospi.iiserpune.ac.in/Nipah/
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.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Nipah virus; Antivirals.