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Site Inhibitors (site + inhibitor)
Selected AbstractsActive Site Inhibitors of HCV NS5B Polymerase.CHEMINFORM, Issue 4 20056-dihydroxypyrimidine-4-carboxylic Acid., Pharmacophore of 2-Thienyl-, The Development Abstract For Abstract see ChemInform Abstract in Full Text. [source] Relationship between Ripening and the Development of Banana Anthracnose Caused by Colletotrichum musae (Berck. and Curt.) ArxJOURNAL OF PHYTOPATHOLOGY, Issue 3 2006M. Chillet Abstract Wound anthracnose caused by Colletotrichum musae is the main disease affecting the quality of export bananas from the French Antilles. Little is known about the effects of ethylene on the development of wound anthracnose and quiescent anthracnose. The results of our experiments with 1-methylcyclopropene (1-MCP), an ethylene receptor site inhibitor, clearly revealed that ethylene was not directly involved in triggering rot development. Quiescent anthracnose symptoms were found to appear only after bananas began ripening. In contrast, wound anthracnose developed just as quickly in ,green 1-MCP-treated bananas' as in ,yellow ripening bananas'. In cases of wound anthracnose, contrary to quiescent anthracnose, rot development was not dependent on the extent of peel ripeness. [source] Development of Selective Bisubstrate-Based Inhibitors Against Protein Kinase C (PKC) Isozymes By Using Dynamic Peptide MicroarraysCHEMBIOCHEM, Issue 12 2009Alex J. Poot Abstract Kinase inhibitors are increasingly important in drug development. Because the majority of current inhibitors target the conserved ATP-binding site, selectivity might become an important issue. This could be particularly problematic for the potential drug target protein kinase C (PKC), of which twelve isoforms with high homology exist in humans. A strategy to increase selectivity is to prepare bisubstrate-based inhibitors that target the more selective peptide-binding site in addition to the ATP-binding site. In this paper a generally applicable, rapid methodology is presented to discover such bisubstrate-based leads. Dynamic peptide microarrays were used to find peptide-binding site inhibitors. These were linked with chemoselective click chemistry to an ATP-binding site inhibitor, and this led to novel bisubstrate structures. The peptide microarrays were used to evaluate the resulting inhibitors. Thus, novel bisubstrate-based inhibitors were obtained that were both more potent and selective compared to their constituent parts. The most promising inhibitor has nanomolar affinity and selectivity towards PKC, amongst three isozymes. [source] On the binding mode of urease active site inhibitors: A density functional studyINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 11 2008M. Leopoldini Abstract The way with which boric acid, a rapid reversible competitive inhibitor, binds the urease active site was explored at density functional B3LYP level of theory. The catalytic core of the enzyme was simulated by two models of different size. In both cases, amino acid residues belonging to the inner and to the outer coordination spheres of nickel ions were replaced by smaller molecular species. Contrary to the experimental indication that attributes the inhibitory ability of this acid to the lack of a nucleophilic attack by the enzyme to the boron atom, we instead found that another possibility exists based on the presence of a strong covalent , bond between boron and urease that we think can be hardly broken to allow any course of the reaction. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulinMEDICINAL RESEARCH REVIEWS, Issue 1 2008Bhabatarak Bhattacharyya Abstract In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine,tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines,tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on , -tubulin. Using the crystal structure of the tubulin,DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 1, 155,183, 2008 [source] Generation and Evaluation of a Homology Model of PfGSK-3ARCHIV DER PHARMAZIE, Issue 6 2009Sebastian Kruggel Abstract Plasmodial GSK-3 is a potential new target for malaria therapy. For a structure-based design project, the three-dimensional information of the designated target is needed. Unfortunately, experimental structure data for plasmodial GSK-3 is not yet available. Homology building can be used to generate such three-dimensional structure data using structure information of a homologous protein. GSK-3 possesses a very flexible ATP-binding site, a fact reflected in the variety of X-ray structures of the human GSK-3, which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK-3, templates for the model building of plasmodial GSK-3 and generated 200 models for each template with different modeling protocols. The quality of the models was evaluated with different tools. The results of these evaluations were used to calculate a rank-by-rank consensus score. The top models of this were used to compile an ensemble of PfGSK-3 models that reflect the flexibility of the ATP-binding site and that will be used for the structure-based design of potential ATP-binding site inhibitors of PfGSK-3. [source] Development of Selective Bisubstrate-Based Inhibitors Against Protein Kinase C (PKC) Isozymes By Using Dynamic Peptide MicroarraysCHEMBIOCHEM, Issue 12 2009Alex J. Poot Abstract Kinase inhibitors are increasingly important in drug development. Because the majority of current inhibitors target the conserved ATP-binding site, selectivity might become an important issue. This could be particularly problematic for the potential drug target protein kinase C (PKC), of which twelve isoforms with high homology exist in humans. A strategy to increase selectivity is to prepare bisubstrate-based inhibitors that target the more selective peptide-binding site in addition to the ATP-binding site. In this paper a generally applicable, rapid methodology is presented to discover such bisubstrate-based leads. Dynamic peptide microarrays were used to find peptide-binding site inhibitors. These were linked with chemoselective click chemistry to an ATP-binding site inhibitor, and this led to novel bisubstrate structures. The peptide microarrays were used to evaluate the resulting inhibitors. Thus, novel bisubstrate-based inhibitors were obtained that were both more potent and selective compared to their constituent parts. The most promising inhibitor has nanomolar affinity and selectivity towards PKC, amongst three isozymes. [source] | ||||||||||