Linked Life Data

11371168

Source:http://linkedlifedata.com/resource/pubmed/id/11371168

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2001-5-23
pubmed:abstractText
The design of new HIV protease inhibitors requires an improved understanding of the physical basis of inhibitor/protein binding. Here, the binding affinities of seven aliphatic cyclic ureas to HIV-1 protease are calculated using a predominant states method and an implicit solvent model based upon finite difference solutions of the Poisson-Boltzmann equation. The calculations are able to reproduce the observed U-shaped trend of binding free energy as a function of aliphatic chain length. Interestingly, the decrease in affinity for the longest chains is attributable primarily to the energy cost of partly desolvating charged aspartic and arginine groups at the mouths of the active site. Even aliphatic chains too short to contact these charged groups directly are subject to considerable desolvation penalties. We are not aware of other systems where binding affinity trends have been attributed to long-ranged electrostatic desolvation of ionized groups. A generalized Born/surface area solvation model yields a much smaller change in desolvation energy with chain length and, therefore, does not reproduce the experimental binding affinity trends. This result suggests that the generalized Born model should be used with caution for complex, partly desolvated systems like protein binding sites. We also find that changing the assumed protonation state of the active site aspartyl dyad significantly affects the computed binding affinity trends. The protonation state of the aspartyl dyad in the presence of cyclic ureas is discussed in light of the observation that the monoprotonated state reproduces the experimental results best.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2836
pubmed:author
pubmed:copyrightInfo
Copyright 2001 Academic Press.
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
309
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
507-17
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Interpreting trends in the binding of cyclic ureas to HIV-1 protease.
pubmed:affiliation
Center for Advanced Research in Biotechnology, 9600 Gudelsky Drive, Rockville, MD 20850, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't