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Allosteric Inhibitors (allosteric + inhibitor)
Selected AbstractsStructural Studies on Hydrogen-Bonding Receptors for Barbiturate Guests That Use Metal Ions as Allosteric InhibitorsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 1 2004Mohammad H. Al-Sayah Abstract Receptor 1 was designed to bind barbiturate substrates through a six-point hydrogen-bonding motif only in the absence of metal allosteric cofactors. It was predicted that the binding of metal ions by bipyridine ligands in 1 would result in a geometric change in the receptor to inhibit substrate recognition. However, receptor 1 showed minimal affinity for the barbiturate guests even in the absence of the metal. Binding studies on model compounds 2, 3, 5, and 6 revealed that the inactivity of 1 is due to an intramolecular hydrogen bond between the N,H donor groups and the nitrogen atoms on the first heterocycle of the bipyridine ligands. This intramolecular hydrogen-bonding was eliminated by altering the position of the tether between the bipyridine ligands and the active site to produce receptor 7. Consequently, the high affinity exhibited by 7 for the barbiturate substrate (Ka = 2.8±0.7 × 103M,1 in 9:1 CD2Cl2/CD3CN) was significantly reduced by the addition of ZnII ions as a negative allosteric co-factor. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Total Synthesis of Pentabromo- and Pentachloropseudilin, and Synthetic Analogues,Allosteric Inhibitors of Myosin ATPase,ANGEWANDTE CHEMIE, Issue 43 2009René Martin Dr. Eine hoch effiziente Silber(I)-katalysierte Cyclisierung von N -Tosylhomopropargylaminen ermöglicht die Totalsynthesen der Titelverbindungen. Die Pseudilin-Derivate sind neuartige Myosin-Inhibitoren. Für Pentabrompseudilin (1) wurde anhand einer Röntgenstrukturanalyse des Inhibitor-Protein-Komplexes eine neue allosterische Bindungstasche in der Dictyostelium -Myosin-2-Motordomäne identifiziert. [source] ChemInform Abstract: Allosteric Inhibitors of Akt1 and Akt2: A Naphthyridinone with Efficacy in an A2780 Tumor Xenograft Model.CHEMINFORM, Issue 42 2008Mark T. Bilodeau Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Benzoxazole Benzenesulfonamides as Allosteric Inhibitors of Fructose-1,6-bisphosphatase.CHEMINFORM, Issue 27 2006Chunqiu Lai Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Flexibility and communication within the structure of the Mycobacterium smegmatis methionyl-tRNA synthetaseFEBS JOURNAL, Issue 19 2010Henrik Ingvarsson Two structures of monomeric methionyl-tRNA synthetase, from Mycobacterium smegmatis, in complex with the ligands methionine/adenosine and methionine, were analyzed by X-ray crystallography at 2.3 Å and at 2.8 Å, respectively. The structures demonstrated the flexibility of the multidomain enzyme. A new conformation of the structure was identified in which the connective peptide domain bound more closely to the catalytic domain than described previously. The KMSKS(301-305) loop in our structures was in an open and inactive conformation that differed from previous structures by a rotation of the loop of about 90° around hinges located at Asn297 and Val310. The binding of adenosine to the methionyl-tRNA synthetase methionine complex caused a shift in the KMSKS domain that brought it closer to the catalytic domain. The potential use of the adenosine-binding site for inhibitor binding was evaluated and a potential binding site for a specific allosteric inhibitor was identified. [source] Inactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesisFEBS JOURNAL, Issue 13 2003Susan Aiston Multiple signalling pathways are involved in the mechanism by which insulin stimulates hepatic glycogen synthesis. In this study we used selective inhibitors of glycogen synthase kinase-3 (GSK-3) and an allosteric inhibitor of phosphorylase (CP-91149) that causes dephosphorylation of phosphorylase a, to determine the relative contributions of inactivation of GSK-3 and dephosphorylation of phosphorylase a as alternative pathways in the stimulation of glycogen synthesis by insulin in hepatocytes. GSK-3 inhibitors (SB-216763 and Li+) caused a greater activation of glycogen synthase than insulin (90% vs. 40%) but a smaller stimulation of glycogen synthesis (30% vs. 150%). The contribution of GSK-3 inactivation to insulin stimulation of glycogen synthesis was estimated to be less than 20%. Dephosphorylation of phosphorylase a with CP-91149 caused activation of glycogen synthase and translocation of the protein from a soluble to a particulate fraction and mimicked the stimulation of glycogen synthesis by insulin. The stimulation of glycogen synthesis by phosphorylase inactivation cannot be explained by either inhibition of glycogen degradation or activation of glycogen synthase alone and suggests an additional role for translocation of synthase. Titrations with the phosphorylase inactivator showed that stimulation of glycogen synthesis by insulin can be largely accounted for by inactivation of phosphorylase over a wide range of activities of phosphorylase a. We conclude that a signalling pathway involving dephosphorylation of phosphorylase a leading to both activation and translocation of glycogen synthase is a critical component of the mechanism by which insulin stimulates hepatic glycogen synthesis. Selective inactivation of phosphorylase can mimic insulin stimulation of hepatic glycogen synthesis. [source] Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discoveryMEDICINAL RESEARCH REVIEWS, Issue 2 2008Qingning Shu Abstract Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme of de novo purine nucleotide biosynthesis and is viewed as an important target in the quest for discovery of drugs in the antiviral, antibacterial and anticancer therapeutic areas. This review focuses on the medicinal chemistry, drug discovery and chemical biology of IMPDH. Examples of IMP and cofactor site-directed inhibitors, allosteric inhibitors and isoform-selective inhibitors are presented. Comparison of IMPDHs from different organisms is also made to facilitate the design of species-selective IMPDH inhibitors for drug discovery. Special emphasis in the review is placed on IMPDH from Mycobacterium tuberculosis. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 2, 219,232, 2008 [source] | ||||||||||