Linked Life Data

8973169

Source:http://linkedlifedata.com/resource/pubmed/id/8973169

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
1997-1-23
pubmed:abstractText
We have previously shown that a small peptide bearing the hydrolytically stable phosphotyrosyl (pTyr) mimetic, (difluorophosphonomethyl) phenylalanine (F2Pmp), is an extremely potent inhibitor of PTP1B, with an IC50 value of 100 nM [Burke, T. R., Kole, H. K., & Roller, P. P. (1994) Biochem. Biophys. Res. Commun. 204, 129-134]. We further demonstrated that removal of the peptide portion and incorporation of the difluorophosphonomethyl moiety onto a naphthalene ring system, but not a phenyl ring system, resulted in good inhibitory potency [Kole, H. K., Smyth, M. S., Russ, P. L., & Burke, T. R., Jr. (1995) Biochem, J. 311, 1025-1031]. In order to understand the structural basis for this inhibition, and to aid in the design of further analogs, we solved the X-ray structure of [1, 1-difluoro-1-(2-naphthalenyl)-methyl]phosphonic acid (6) complexed within the catalytic site of PTP1B, solved to 2.3 A resolution. In addition to showing the manner in which the phosphonate group is held within the catalytic site, the X-ray structure also revealed extensive hydrophobic interactions with the naphthalene ring system, beyond that possible with an analog bearing a single phenyl ring. It is further evident that, of the two fluorine atoms, the pro-R alpha-fluorine interacts with the enzyme to a significantly greater degree than the pro-S alpha-fluorine, forming a hydrogen bond to Phe 182. On the basis of a computer-assisted molecular modeling analysis, it was determined that addition of a hydroxyl to the naphthyl 4-position, giving [1, 1-difluoro-1-[2-(4-hydroxynaphthalenyl)] methyl]phosphonic acid (8), could potentially replace a water molecule situated in the PTP1B-6 complex, thereby allowing new hydrogen-bonding interactions with Lys 120 and Tyr 46. Compound 8 was therefore prepared and found to exhibit a doubling of affinity (Ki = 94 microM) relative to parent unsubstituted 6 (Ki = 179 microM), supporting, in principle, the development of high-affinity ligands based on molecular modeling analysis of the enzyme-bound parent.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
15989-96
pubmed:dateRevised
2009-9-29
pubmed:meshHeading
pubmed-meshheading:8973169-Binding Sites, pubmed-meshheading:8973169-Calorimetry, pubmed-meshheading:8973169-Computer Simulation, pubmed-meshheading:8973169-Crystallography, X-Ray, pubmed-meshheading:8973169-Cysteine, pubmed-meshheading:8973169-Drug Design, pubmed-meshheading:8973169-Enzyme Inhibitors, pubmed-meshheading:8973169-Kinetics, pubmed-meshheading:8973169-Models, Molecular, pubmed-meshheading:8973169-Naphthalenes, pubmed-meshheading:8973169-Phosphonic Acids, pubmed-meshheading:8973169-Phosphotyrosine, pubmed-meshheading:8973169-Point Mutation, pubmed-meshheading:8973169-Protein Conformation, pubmed-meshheading:8973169-Protein Structure, Secondary, pubmed-meshheading:8973169-Protein Tyrosine Phosphatases, pubmed-meshheading:8973169-Recombinant Proteins, pubmed-meshheading:8973169-Serine
pubmed:year
1996
pubmed:articleTitle
Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design.
pubmed:affiliation
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't