Locking the 150-cavity open: in silico design and verification of influenza neuraminidase inhibitors

Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and mo...

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Bibliographic Details
Published in:PloS one 2013-08, Vol.8 (8), p.e73344-e73344
Main Authors: Han, Nanyu, Mu, Yuguang
Format: Article
Language:English
Subjects:
Bioinformatics
Control systems
Control systems design
Design
Drug Design
Enzyme Inhibitors - chemistry
Epidemics
Exo-a-sialidase
Fragmentation
Humans
Influenza
Influenza A Virus, H1N1 Subtype - enzymology
Inhibitors
Libraries
Ligands
Medical screening
Methods
Molecular docking
Molecular Docking Simulation
Molecular dynamics
Mutation
Neuraminidase - antagonists & inhibitors
Neuraminidase - chemistry
Proteins
Simulation
Studies
Vaccines
Viruses
Zanamivir
Zanamivir - chemistry
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Summary:Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0073344