Dokumentenart: | Artikel | ||||||
---|---|---|---|---|---|---|---|
Titel eines Journals oder einer Zeitschrift: | Biochemical Pharmacology | ||||||
Verlag: | PERGAMON-ELSEVIER SCIENCE LTD | ||||||
Ort der Veröffentlichung: | OXFORD | ||||||
Band: | 82 | ||||||
Nummer des Zeitschriftenheftes oder des Kapitels: | 4 | ||||||
Seitenbereich: | S. 358-370 | ||||||
Datum: | 2011 | ||||||
Institutionen: | Chemie und Pharmazie > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König Chemie und Pharmazie > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König | ||||||
Sonstige Projekte: | DFG | ||||||
Identifikationsnummer: |
| ||||||
Stichwörter / Keywords: | SOLUBLE GUANYLYL CYCLASE; NUCLEOSIDE 5'-TRIPHOSPHATES; EDEMA FACTOR; DIFFERENTIAL INTERACTIONS; BACILLUS-ANTHRACIS; FORSKOLIN ANALOGS; DRUG DISCOVERY; ISOFORMS; INHIBITION; PROTEIN; Adenylyl Cyclase; MANT-nucleotides; Fluorescence spectroscopy; Molecular modelling; Conformational landscape | ||||||
Dewey-Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik > 540 Chemie | ||||||
Status: | Veröffentlicht | ||||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||||
An der Universität Regensburg entstanden: | Ja | ||||||
Dokumenten-ID: | 21740 |
Zusammenfassung
Membranous adenylyl cyclases (ACs) play a key role in signal transduction and are promising drug targets. In previous studies we showed that 2',3'-(O)-(N-methylanthraniloyl) (MANT)-substituted nucleotides are potent AC inhibitors. The aim of this study was to provide systematic structure-activity relationships for 21 (M)ANT-substituted nucleotides at the purified catalytic AC subunit heterodimer ...

Zusammenfassung
Membranous adenylyl cyclases (ACs) play a key role in signal transduction and are promising drug targets. In previous studies we showed that 2',3'-(O)-(N-methylanthraniloyl) (MANT)-substituted nucleotides are potent AC inhibitors. The aim of this study was to provide systematic structure-activity relationships for 21 (M)ANT-substituted nucleotides at the purified catalytic AC subunit heterodimer VC1:IIC2, the VC1:VC1 homodimer and recombinant ACs 1, 2 and 5. (M)ANT-nucleotides inhibited fully activated VC1:IIC2 in the order of affinity for bases hypoxanthine > uracil > cytosine > adenine similar to guanine >> xanthine. Omission of a hydroxyl group at the 2' or 3'-position reduced inhibitor potency as did introduction of a gamma-thiophosphate group or omission of the gamma-phosphate group. Substitution of the MANT-group by an ANT-group had little effect on affinity. Although all nucleotides bound to VC1:IIC2 similarly according to the tripartite pharmacophore model with a site for the base, the ribose, and the phosphate chain, nucleotides exhibited subtle differences in their binding modes as revealed by fluorescence spectroscopy and molecular modelling. MANT-nucleotides also differentially interacted with the VC1:VC1 homodimer as assessed by fluorescence spectroscopy and modelling. Similar structure-activity relationships as for VC1:IIC2 were obtained for recombinant ACs 1,2 and 5, with AC2 being the least sensitive AC isoform in terms of inhibition. Overall, ACs possess a broad base-specificity with no preference for the "cognate" base adenine as verified by enzyme inhibition, fluorescence spectroscopy and molecular modelling. These properties of ACs are indicative for ligand-specific conformational landscapes that extend to the VC1:VC1 homodimer and should facilitate development of non-nucleotide inhibitors. (C) 2011 Elsevier Inc. All rights reserved.
Metadaten zuletzt geändert: 29 Sep 2021 07:38