Linked Life Data

16892339

Source:http://linkedlifedata.com/resource/pubmed/id/16892339

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2006-8-7
pubmed:abstractText
The inhibition of cytochrome P450 3A4 (CYP3A4) by small molecules is a major mechanism associated with undesired drug-drug interactions, which are responsible for a substantial number of late-stage failures in the pharmaceutical drug-development process. For a quantitative prediction of associated pharmacokinetic parameters, a computational model was developed that allows prediction of the inhibitory potential of 48 structurally diverse molecules. Based on the experimental structure of CYP3A4, possible binding modes were first sampled by using automated docking (Yeti software) taking protein flexibility into account. The results are consistent with both X-ray crystallographic data and data from metabolic studies. Next, an ensemble of energetically favorable orientations was composed into a 4D dataset for use as input for a multidimensional QSAR technique (Raptor software). A dual-shell binding-site model that allows an explicit induced fit was then generated by using hydrophobicity scoring and hydrogen-bond propensity. The simulation reached a cross-validated r2 value of 0.825 and a predictive r2 value of 0.659. On average, the predicted binding affinity of the training ligands deviates by a factor of 2.7 from the experiment; those of the test set deviate by a factor of 3.8 in Ki.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1860-7179
pubmed:author
pubmed:issnType
Print
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
73-81
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Prediction of small-molecule binding to cytochrome P450 3A4: flexible docking combined with multidimensional QSAR.
pubmed:affiliation
Biographics Laboratory 3R, Friedensgasse 35, 4056 Basel, Switzerland. markus@biograf.ch
pubmed:publicationType
Journal Article