Linked Life Data

11543680

Source:http://linkedlifedata.com/resource/pubmed/id/11543680

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2001-9-6
pubmed:abstractText
Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which are unable to coordinate the zinc ion, a conclusion that resulted in the postulation of one or two hitherto unknown aryl binding sites. No indication has been given about the spatial location of these novel binding sites. Employing flexible docking of several non-thiol farnesyltransferase inhibitors known from the literature and some model compounds based on our benzophenone scaffold as well as performing GRID searches, we have identified two regions in the farnesyltransferase's active site which we suggest being the postulated aryl binding sites. One aryl binding region is located in close proximity to the zinc ion and is defined by the aromatic side chains of Tyr 300beta, Trp 303beta, Tyr 361beta, and Tyr 365beta. The second aryl binding site is defined by the side chains of Tyr 300beta, Leu 295beta, Lys 294beta, Lys 353beta, and Lys 356beta. This second aryl binding site has been used for the design of a non-thiol farnesyltransferase inhibitor (9c) with an IC(50) of 35 nM.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3117-24
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Exploration of novel aryl binding sites of farnesyltransferase using molecular modeling and benzophenone-based farnesyltransferase inhibitors.
pubmed:affiliation
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't