Linked Life Data

19778066

Source:http://linkedlifedata.com/resource/pubmed/id/19778066

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
42
pubmed:dateCreated
2009-11-20
pubmed:abstractText
A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free-energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-alphaMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However, as in the EGFR example, the binding affinity may diminish if the free-energy increase due to the removal of the bound water molecule is not more than compensated by the additional interactions of the water-displacing moiety. For accurate computation of the effects of ligand modifications, a complete thermodynamic analysis is shown to be needed. It requires identification of the location of water molecules in the protein-ligand interface and evaluation of the free-energy changes associated with their removal and with the introduction of the ligand modification. Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1520-5126
pubmed:author
pubmed:issnType
Electronic
pubmed:day
28
pubmed:volume
131
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
15403-11
pubmed:dateRevised
2010-12-3
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization.
pubmed:affiliation
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural