Linked Life Data

10579815

Source:http://linkedlifedata.com/resource/pubmed/id/10579815

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
1999-12-17
pubmed:abstractText
A novel strategy to understand affinity and selectivity for enzyme inhibitors using information from ligands and target protein 3D structures is described. It was applied to 2-arylsulfonyl-1,2,3, 4-tetrahydro-isoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinases MMP-3 (stromelysin-1) and MMP-8 (human neutrophil collagenase). As the first step, consistent and predictive 3D-QSAR models were derived using CoMFA, CoMSIA, and GRID/Golpe approaches, leading to the identification of binding regions where steric, electronic, or hydrophobic effects are important for affinity. These models were validated using multiple analyses using two or five randomly chosen cross-validation groups and randomizations of biological activities. Second, 3D-QSAR models were derived based on the affinity ratio IC(50)(MMP-8)/IC(50)(MMP-3), allowing the identification of key ligand determinants for selectivity toward one of both enzymes. In addition to this ligands' view, the third step encompasses a chemometrical approach based on principal component analysis (PCA) of multivariate GRID descriptors to uncover the major differences between both protein binding sites with respect to their GRID probe interaction pattern. The resulting information, based on the accurate knowledge of the target protein 3D structures, led to a consistent picture in good agreement with experimentally observed differences in selectivity toward MMP-8 or MMP-3. The interpretation of all three classes of statistical models leads to detailed SAR information for MMP inhibitors, which is in agreement with available data for binding site topologies, ligand affinities, and selectivities. Thus the combined chemical analyses provide guidelines and accurate activity predictions for designing novel, selective MMP inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4506-23
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Affinity and selectivity of matrix metalloproteinase inhibitors: a chemometrical study from the perspective of ligands and proteins.
pubmed:affiliation
Hoechst Marion Roussel, Chemical Research, D-65926 Frankfurt am Main, Germany. hans.matter@hmrag.com
pubmed:publicationType
Journal Article