Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
MOLECULAR ELECTROSTATIC POTENTIAL ANALYSIS FOR ENZYMATIC SUBSTRATES, COMPETITIVE INHIBITORS, AND TRANSITION-STATE INHIBITORS
Autore:
BAGDASSARIAN CK; SCHRAMM VL; SCHWARTZ SD;
Indirizzi:
YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT PHYSIOL & BIOPHYS BRONX NY10461 YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT PHYSIOL & BIOPHYS BRONX NY10461 YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT BIOCHEM BRONX NY 10461
Titolo Testata:
Journal of the American Chemical Society
fascicolo: 37, volume: 118, anno: 1996,
pagine: 8825 - 8836
SICI:
0002-7863(1996)118:37<8825:MEPAFE>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMP NUCLEOSIDASE; ADENOSINE-DEAMINASE; SURFACES; SIMILARITY; ANALOG; DESIGN; YEAST; RECOGNITION; SPECIFICITY; ABINITIO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
50
Recensione:
Indirizzi per estratti:
Citazione:
C.K. Bagdassarian et al., "MOLECULAR ELECTROSTATIC POTENTIAL ANALYSIS FOR ENZYMATIC SUBSTRATES, COMPETITIVE INHIBITORS, AND TRANSITION-STATE INHIBITORS", Journal of the American Chemical Society, 118(37), 1996, pp. 8825-8836

Abstract

Recent advances in the application of kinetic isotope effects to enzyme-catalyzed reactions have provided reliable information for enzymatic transition state structures, A method is presented for quantifying the similarity of substrates and inhibitors with their enzyme-stabilized transition states. On the basis of transition-state stabilization theory for enzymatic reactions, molecules most similar to the transitionstate structure bind with greatest affinity, Molecular similarity measures are applied to compare substrates, competitive inhibitors, and transition state inhibitors with the transition state structures stabilized by the enzymes AMP deaminase, adenosine deaminase, and AMP nucleosidase. (R)- and (S)-Coformycin 5'-phosphate are inhibitors for AMP deaminase, with the R-species superior to its enantiomer. Formycin 5'-phosphate 4-aminopyrazolo [3,4-d] pyrimidine-1-ribonucleotide, and tubercidin 5'-phosphate inhibit AMP nucleosidase. The transition state for adenosine deaminase is analogous to that for AMP deaminase, allowing analysis of the tight-binding hydrate of purine ribonucleoside and of aweaker inhibitor, 1,6-dihydropurine ribonucleoside. The basis for ranking molecules for similarity to the transition state is the distribution of electrostatic potential at the molecular van der Waals surface. Spatial properties of a molecule are described through the topographyof the surface, while the electrostatics capture ionic, hydrogen-bonding, and hydrophobic features. A test molecule is compared with the transition state by orienting the two species so that their van der Waals surfaces are maximally coincident. At this orientation, a single measure sensitive both to the electrostatic potential and its spatial distribution is used to rank the electronic similarity. For AMP deaminase, adenosine deaminase, and AMP nucleosidase, the transition state inhibitors are quantitatively more similar to the transition states than are the substrates. A strong correlation between the binding free energies and the similarity measures is found for most of the transition-state inhibitors in all three enzyme systems. This method is useful in the logical design of transition state inhibitors and may be applied tosimilarity searches of chemical libraries.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 17:05:36