Linked Life Data

12801228

Source:http://linkedlifedata.com/resource/pubmed/id/12801228

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2003-6-12
pubmed:abstractText
A new class of very potent inhibitors of cytosol leucine aminopeptidase (LAP), a member of the metalloprotease family, is described. The X-ray structure of bovine lens leucine aminopeptidase complexed with the phosphonic acid analogue of leucine (LeuP) was used for structure-based design of novel LAP inhibitors and for the analysis of their interactions with the enzyme binding site. The inhibitors were designed by modification of phosphonic group in the LeuP structure toward finding the substituents bound at the S' side of the enzyme. This resulted in two classes of compounds, the phosphonamidate and phosphinate dipeptide analogues, which were synthesized and evaluated as inhibitors of the enzyme. The in vitro kinetic studies for the phosphinate dipeptide analogues revealed that these compounds belong to the group of the most effective LAP inhibitors found so far. Their further modification at the P1 position resulted in more active inhibitors, hPheP[CH(2)]Phe and hPheP[CH(2)]Tyr (K(i) values 66 nM and 67 nM, respectively, for the mixture of four diastereomers). The binding affinities of these inhibitors toward the enzyme are the highest, if considering all compounds containing a phosphorus atom that mimic the transition state of the reaction catalyzed by LAP. To evaluate selectivity of the designed LAP inhibitors, additional tests toward aminopeptidase N (APN) were performed. The key feature, which determines their selectivity, is structure at the P1' position. Aromatic and aliphatic substituents placed at this position strongly interact with the LAP S1' binding pocket, while a significant increase in binding affinity toward APN was observed for compounds containing aromatic versus leucine side chains at the P1' position. The most selective inhibitor, hPheP[CH(2)]Leu, binds to LAP with 15 times higher affinity than to APN. One of the studied compounds, hPheP[CH(2)]Tyr, appeared to be very potent inhibitor of APN (K(i) = 36 nM for the mixture of four diastereomers). The most promising LAP inhibitors designed by computer-aided approach, the phosphonamidate dipeptide analogues, were unstable at pH below 12, because of the P-N bond decomposition, which excluded the possibility of determination of their binding affinities toward LAP.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2641-55
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12801228-Animals, pubmed-meshheading:12801228-Antigens, CD13, pubmed-meshheading:12801228-Binding Sites, pubmed-meshheading:12801228-Cattle, pubmed-meshheading:12801228-Crystallography, X-Ray, pubmed-meshheading:12801228-Dipeptides, pubmed-meshheading:12801228-Drug Stability, pubmed-meshheading:12801228-Enzyme Inhibitors, pubmed-meshheading:12801228-Lens, Crystalline, pubmed-meshheading:12801228-Leucine, pubmed-meshheading:12801228-Leucyl Aminopeptidase, pubmed-meshheading:12801228-Models, Molecular, pubmed-meshheading:12801228-Molecular Structure, pubmed-meshheading:12801228-Organophosphorus Compounds, pubmed-meshheading:12801228-Phosphinic Acids, pubmed-meshheading:12801228-Phosphonic Acids, pubmed-meshheading:12801228-Protein Binding, pubmed-meshheading:12801228-Stereoisomerism, pubmed-meshheading:12801228-Structure-Activity Relationship
pubmed:year
2003
pubmed:articleTitle
The most potent organophosphorus inhibitors of leucine aminopeptidase. Structure-based design, chemistry, and activity.
pubmed:affiliation
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wroc?aw University of Technology, Wybrzeze Wyspia?skiego 27, 50-370 Wroc?aw, Poland. jola@neon.ch.pwr.wroc.pl
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't