NDLI: The Influence of 150-Cavity Binders on the Dynamics of Influenza A Neuraminidases as Revealed by Molecular Dynamics Simulations and Combined Clustering

Content Provider	PubMed Central
Author	Greenway, Kyle T. Legresley, Eric B. Pinto, B. Mario
Editor	Agarwal, Pratul K.
Copyright Year	2013
Abstract	Neuraminidase inhibitors are the main pharmaceutical agents employed for treatments of influenza infections. The neuraminidase structures typically exhibit a 150-cavity, an exposed pocket that is adjacent to the catalytic site. This site offers promising additional contact points for improving potency of existing pharmaceuticals, as well as generating entirely new candidate inhibitors. Several inhibitors based on known compounds and designed to interact with 150-cavity residues have been reported. However, the dynamics of any of these inhibitors remains unstudied and their viability remains unknown. This work reports the outcome of long-term, all-atom molecular dynamics simulations of four such inhibitors, along with three standard inhibitors for comparison. Each is studied in complex with four representative neuraminidase structures, which are also simulated in the absence of ligands for comparison, resulting in a total simulation time of 9.6µs. Our results demonstrate that standard inhibitors characteristically reduce the mobility of these dynamic proteins, while the 150-binders do not, instead giving rise to many unique conformations. We further describe an improved RMSD-based clustering technique that isolates these conformations – the structures of which are provided to facilitate future molecular docking studies – and reveals their interdependence. We find that this approach confers many advantages over previously described techniques, and the implications for rational drug design are discussed.
Related Links	http://dx.doi.org/10.1371/journal.pone.0059873
Starting Page	59873
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	3
Volume Number	8
Language	English
Publisher	Public Library of Science
Publisher Date	2013-03-27
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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