Predicting and designing therapeutics against the Nipah virus
| Autor: | Sanjana Nair, Ankit Roy, Gulzar Singh, Kaustubh Amritkar, Neelesh Soni, Tejashree Rajaram Kanitkar, Mallur S. Madhusudhan, Neeladri Sen, Shreyas Supekar |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Conformation RC955-962 Protein Data Bank (RCSB PDB) Peptide Plasma protein binding 01 natural sciences Biochemistry Physical Chemistry Database and Informatics Methods Protein Structure Databases 0302 clinical medicine Protein structure Arctic medicine. Tropical medicine Biochemical Simulations Macromolecular Structure Analysis Free Energy chemistry.chemical_classification 0303 health sciences education.field_of_study Organic Compounds Physics Small molecule 3. Good health Chemistry Infectious Diseases Drug development Proteome Physical Sciences Thermodynamics Engineering and Technology Public aspects of medicine RA1-1270 Sequence Analysis Research Article Biotechnology Protein Binding Protein Structure Bioinformatics 030231 tropical medicine Population Sequence Databases Bioengineering Computational biology Biology Molecular Dynamics Simulation 010402 general chemistry Research and Analysis Methods Antiviral Agents Virus Protein–protein interaction 03 medical and health sciences Viral Proteins education Protein Interactions Molecular Biology 030304 developmental biology Chemical Bonding Organic Chemistry Public Health Environmental and Occupational Health Chemical Compounds Nipah Virus Biology and Life Sciences Computational Biology Proteins Hydrogen Bonding Virology 0104 chemical sciences 030104 developmental biology Biological Databases chemistry Docking (molecular) Small Molecules |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 13, Iss 12, p e0007419 (2019) |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | 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. Author summary 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. |
| Databáze: | OpenAIRE |
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