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Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble

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dc.contributor.author Landon, Melissa R en_US
dc.contributor.author Amaro, Rommie E en_US
dc.contributor.author Baron, Riccardo en_US
dc.contributor.author Ngan, Chi Ho en_US
dc.contributor.author Ozonoff, David en_US
dc.contributor.author Andrew McCammon, J en_US
dc.contributor.author Vajda, Sandor en_US
dc.date.accessioned 2011-12-29T22:48:41Z
dc.date.available 2011-12-29T22:48:41Z
dc.date.issued 2011-12-29
dc.identifier.citation Landon, Melissa R, Rommie E Amaro, Riccardo Baron, Chi Ho Ngan, David Ozonoff, J Andrew McCammon, Sandor Vajda. "Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble" Chemical Biology & Drug Design 71(2):106-116. (2008) en_US
dc.identifier.issn 1747-0285 en_US
dc.identifier.uri http://hdl.handle.net/2144/2605
dc.description.abstract The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative 'hot spots' within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain. en_US
dc.description.sponsorship National Institutes of Health (R01-HM064700, F32-GM077729, GM31749); National Science Foundation (CHE060073N, MCB-0506593, MCA93S013); Howard Hughes Medical Institute; San Diego Supercomputing Center, Accelrys, Inc.; W.M. Keck Foundation; National Biomedical Computational Resource Center for Theoretical Biological Physics en_US
dc.language.iso en en_US
dc.publisher Blackwell Publishing Ltd en_US
dc.subject Computational solvent mapping en_US
dc.subject Ensemble-based drug design en_US
dc.subject H5N1 en_US
dc.subject Hot spot en_US
dc.subject Molecular dynamics en_US
dc.subject Neuraminidase en_US
dc.subject Receptor flexibility en_US
dc.subject RMSD clustering en_US
dc.title Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble en_US
dc.type article en_US
dc.identifier.doi 10.1111/j.1747-0285.2007.00614.x en_US
dc.identifier.pubmedid 18205727 en_US
dc.identifier.pmcid 2438278 en_US


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