Linked Life Data

12510879

Source:http://linkedlifedata.com/resource/pubmed/id/12510879

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2003-1-3
pubmed:abstractText
This study describes the use of alignment-independent descriptors for obtaining qualitative and quantitative predictions of the competitive inhibition of CYP2C9 on a serie of highly structurally diverse compounds. This was accomplished by calculating alignment independent descriptors in ALMOND. These GRid INdependent Descriptors (GRIND) represent the most important GRID-interactions as a function of the distance instead of the actual position of each grid-point. The experimental data was determined under uniform conditions. The inhibitor data set consists of 35 structurally diverse competitive stereospecific inhibitors of the cytochrome P450 2C9 and the non -inhibitor data set of 46 compounds. In a PLS discriminant analysis 21 inhibitors and 21 non-inhibitors (1 and 0 as activities) were analyzed using the ALMOND program obtaining a model with an r2 of 0.74 and a cross-validation value (q2) of 0.64. The model was externally validated with 39 compounds (14 inhibitors/25 non-inhibitors). 74% of the compounds were correctly predicted and an additional 13% was assigned to a borderline cluster. Thereafter, a model for quantitative predictions was generated by a PLS analysis of the GRIND descriptors using the experimental Ki-value for 21 of the competitive inhibitors (r2 = 0.77, q2 = 0.60). The model was externally validated using 12 compounds and predicted 11 out of 12 of the Ki-values within 0.5 log units. The discriminant model will be useful in screening for CYP2C9 inhibitors from large compound collections. The 3D-QSAR model will be used during lead optimization to avoid chemistry that result in inhibition of CYP2C9.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0920-654X
pubmed:author
pubmed:issnType
Print
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
443-58
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
pubmed:affiliation
Department of Organic Pharmaceutical Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden. Lovisa.Afzelius@astrazeneca.com
pubmed:publicationType
Journal Article, Comparative Study