Linked Life Data

14667217

Source:http://linkedlifedata.com/resource/pubmed/id/14667217

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2003-12-11
pubmed:abstractText
Development of the new generation of therapeutics against the influenza viral coat protein neuraminidase is a response to the continuing threat of influenza epidemics. A variety of structurally similar compounds have been reported that vary greatly in their ability to inhibit neuraminidase, a critical enzyme that cleaves sialic acid and promotes virion release. To determine how neuraminidase exhibits this wide range of affinities with structurally similar compounds, molecular dynamic simulations, coupled with free energy calculations, were used to determine the binding components of a series of neuraminidase inhibitors. Using four cocrystal structures of neuraminidase-inhibitor complexes, we examined the structural and energetic components of ligand potency and selectivity. An in-depth energetic analysis, including internal energy, entropy, and nonbonded interactions, reveals that potency of ligand binding is governed by nonpolar contacts. Electrostatic components generally oppose binding, although two of the best inhibitors use electrostatic interactions to orient the ligand. This investigation suggests that the enhanced selectivity and potency of the better ligands may arise from an improved positioning of their ligand atoms in the active site due to polar and hydrophobic functionalities. Simulations that included crystal water molecules in the active site indicate that the more potent ligands make less use of water-mediated interactions.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
18
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5628-37
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Investigation of neuraminidase-substrate recognition using molecular dynamics and free energy calculations.
pubmed:affiliation
Department of Pharmaceutical Chemistry, Chemistry and Chemical Biology Program, University of California-San Francisco, 600 16th Street, Box 2240, San Francisco, CA 94143-2240, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.