Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors

Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China
International Journal of Molecular Sciences (Impact Factor: 2.86). 12/2010; 11(12):4932-51. DOI: 10.3390/ijms11124932
Source: PubMed


The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH(3) (+)) and C-terminus (COO(-)) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N-terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.

Download full-text


Available from: Zhiwei Yang, Nov 05, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Casein kinase 2 (CK2) is a ubiquitous serine-threonine protein kinase, which of specific substrates are involved in the regulation of several vital physiological processes in plants. Detailed studies of CK2 have focused on the herbaceous species of Arabidopsis, maize, however, it has remained largely unexplored in woody trees. In this study, we identified the four genes encoding CK2α subunits in a search for Populus genome. Reorganization of CK2α genes in Populus genome showed that its multiple copies are resulted from segmental duplication and tandem duplication events. Phylogenetic and in silico expression analysis indicated that, the divergence was present among poplar CK2α genes, dividing into type I and type II, and each type represented by relatively consistent expression profile. Further docking and molecular dynamic simulations revealed that the poplar CK2α specifically recognize the special pentapeptides (XES/T*DD) of natural substrates and then introduce the phosphorylation of C-terminal region of poplar P-protein. This study will provide the insight into the understanding of interacting mechanism of poplar CK2α with their natural substrates, and be of valuable resource for further assessment of the function of phosphorylation of P-protein in woody plants.
    Full-text · Article · Nov 2011 · African journal of microbiology research

  • No preview · Article · Nov 2011 · African journal of microbiology research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, the anti-influenza A (H2N2) virus activity of patchouli alcohol was studied in vitro, in vivo and in silico. The CC₅₀ of patchouli alcohol was above 20 µM. Patchouli alcohol could inhibit influenza virus with an IC₅₀ of 4.03 ± 0.23 µM. MTT assay showed that the inhibition by patchouli alcohol appears strongly after penetration of the virus into the cell. In the influenza mouse model, patchouli alcohol showed obvious protection against the viral infection at a dose of 5 mg/kg/day. Flexible docking and molecular dynamic simulations indicated that patchouli alcohol was bound to the neuraminidase protein of influenza virus, with an interaction energy of -40.38 kcal mol⁻¹. The invariant key active-site residues Asp151, Arg152, Glu119, Glu276 and Tyr406 played important roles during the binding process. Based on spatial and energetic criteria, patchouli alcohol interfered with the NA functions. Results presented here suggest that patchouli alcohol possesses anti-influenza A (H2N2) virus properties, and therefore is a potential source of anti-influenza agents for the pharmaceutical industry.
    Preview · Article · Dec 2011 · Molecules
Show more