a proposal for a structural model of the feline calicivirus protease bound to the substrate peptide under physiological conditions

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ID: 253702
2017
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Ranked #641 of 875 articles by views in journal of magnetic resonance (san diego, calif : 1997)

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Abstract
Feline calicivirus (FCV) protease functions to cleave viral precursor proteins during productive infection. Previous studies have mapped a protease-coding region and six cleavage sites in viral precursor proteins. However, how the FCV protease interacts with its substrates remains unknown. To gain insights into the interactions, we constructed a molecular model of the FCV protease bound with the octapeptide containing a cleavage site of the capsid precursor protein by homology modeling and docking simulation. The complex model was used to screen for the substrate mimic from a chemical library by pharmacophore-based in silico screening. With this structure-based approach, we identified a compound that has physicochemical features and arrangement of the P3 and P4 sites of the substrate in the protease, is predicted to bind to FCV proteases in a mode similar to that of the authentic substrate, and has the ability to inhibit viral protease activity in vitro and in the cells, and to suppress viral replication in FCV-infected cells. The complex model was further subjected to molecular dynamics simulation to refine the enzyme-substrate interactions in solution. The simulation along with a variation study predicted that the authentic substrate and anti-FCV compound share a highly conserved binding site. These results suggest the validity of our in silico model for elucidating protease-substrate interactions during FCV replication and for developing antivirals.
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yokoyama2017frontiersa Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Masaru Yokoyama, Tomoichiro Oka, Hirotaka Takagi, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Yukinobu Tohya, Hironori Sato
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Journal journal of magnetic resonance (san diego, calif : 1997)
Year 2017
DOI
10.3389/fmicb.2017.01383
URL
http://journal.frontiersin.org/article/10.3389/fmicb.2017.01383/full
Keywords
protease

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