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41.
E. Eichwald A. Fodor Bruno Kisch R. Weinland H. Friedenthal W. Löb F. Machatschek Hesse und Grossmann 《Fresenius' Journal of Analytical Chemistry》1919,58(12):548-549
Ohne Zusammenfassung 相似文献
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Fragment‐Based De Novo Design Reveals a Small‐Molecule Inhibitor of Helicobacter Pylori HtrA
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Thomas P. Schmidt Dr. Manja Böhm Katharina Stutz Daniel Reker Dr. Bernhard Pfeiffer Prof. Dr. Karl‐Heinz Altmann Prof. Dr. Steffen Backert Prof. Dr. Silja Wessler Prof. Dr. Gisbert Schneider 《Angewandte Chemie (International ed. in English)》2015,54(35):10244-10248
Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity. 相似文献
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Philipp M. Cromm Jochen Spiegel Dr. Tom N. Grossmann Prof. Dr. Herbert Waldmann 《Angewandte Chemie (International ed. in English)》2015,54(46):13516-13537
Small GTPases are a family of GDP‐/GTP‐binding proteins that serve as biomolecular switches inside cells to control a variety of essential cellular processes. Aberrant function and regulation of small GTPases is associated with a variety of human diseases, thus rendering these proteins highly interesting targets in drug discovery. However, this class of proteins has been considered “undruggable”, as intensive decade‐long efforts did not yield clinically relevant direct modulators of small GTPases. Recently, the targeting of small GTPases has gained fresh impetus through the discovery of novel transient cavities on the protein surfaces and the application of new targeting strategies. Besides Ras proteins, other small GTPases have attracted increased attention since improved biological insight in combination with novel targeting strategies identified them as promising targets in drug discovery. This Review gives an overview of relevant aspects of the superfamily of small GTPases and summarizes recent progress and perspectives for the direct modulation of these challenging targets. 相似文献
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Dr. Tiago Rodrigues Nadine Hauser Daniel Reker Dr. Michael Reutlinger Tiffany Wunderlin Dr. Jacques Hamon Dr. Guido Koch Prof. Dr. Gisbert Schneider 《Angewandte Chemie (International ed. in English)》2015,54(5):1551-1555
We report a multi‐objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer‐generated 5‐HT2B receptor ligands with accurately predicted target‐binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand‐efficient 5‐HT2B modulators with sustained cell‐based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics‐assisted synthesis enables the swift generation of small molecules with the desired polypharmacology. 相似文献
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Reliable determination of protein-protein interaction sites is of critical importance for structure-based design of small molecules modulating protein function through macromolecular interfaces. We present an alignment-free computational method for prediction of protein-protein interface residues. The method ("iPred") is based on a knowledge-based scoring function adapted from the field of protein folding and small molecule docking. Based on a training set of 394 hetero-dimeric proteins iPred achieves sustained accuracy on an external unbound test set. Prediction robustness was assessed from more than 1500 diverse complexes containing homo- and hetero-dimers. The technique does not rely on sequence conservation, so that rapid interface identification is possible even for proteins for which homologs are unknown or lack conserved residue patterns in interface region. Functional "hot-spot" residues are enriched among the predicted interface residues, rendering the method predestined for macromolecular binding site identification and drug design studies aiming at modulating protein-protein interaction that might influence protein function. For a comparative structural model of peptidase HtrA from Helicobacter pylori, we performed mutation studies for predicted hot-spot residues, which were confirmed as functionally relevant for HtrA activity or oligomerization. 相似文献