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New antimalarial drugs 总被引:6,自引:0,他引:6
Wiesner J Ortmann R Jomaa H Schlitzer M 《Angewandte Chemie (International ed. in English)》2003,42(43):5274-5293
Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease. 相似文献
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Fragment‐Based Drug Design Facilitated by Protein‐Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin 下载免费PDF全文
Dr. Milon Mondal M. Yagiz Unver Dr. Asish Pal Matthijs Bakker Stephan P. Berrier Prof. Dr. Anna K. H. Hirsch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(42):14826-14830
There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein‐templated click chemistry is an efficient and powerful method that accelerates the hit‐identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm , represents the first example of triazole‐based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets. 相似文献
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Meggers E 《Angewandte Chemie (International ed. in English)》2011,50(11):2442-2448
The tremendous challenge presented by the specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This Minireview discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the underlying chemical scaffolds. These include complicated natural-product-like organic molecules, stable octahedral metal complexes, fullerenes, carboranes, polymetallic clusters, and even polymers. Thus the whole repertoire of organic, inorganic, and macromolecular chemistry can be applied to tackle the problem of target-specific enzyme inhibition. 相似文献
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《Angewandte Chemie (International ed. in English)》2017,56(48):15200-15209
Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small‐molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding‐site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ϵ ‐amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery. 相似文献
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Pablo Martín‐Gago Christian A. Olsen 《Angewandte Chemie (International ed. in English)》2019,58(4):957-966
Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off‐target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context‐specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery. 相似文献
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Overcoming the Unexpected Functional Inversion of a PqsR Antagonist in Pseudomonas aeruginosa: An In Vivo Potent Antivirulence Agent Targeting pqs Quorum Sensing 下载免费PDF全文
Cenbin Lu Christine K. Maurer Benjamin Kirsch Dr. Anke Steinbach Prof. Dr. Rolf W. Hartmann 《Angewandte Chemie (International ed. in English)》2014,53(4):1109-1112
The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P. aeruginosa is revealed, which is mediated by a bacterial signal molecule synthase and responsible for low cellular potency. Blockade of the susceptible position led to the discovery of the first antivirulence compound that is potent in vivo and targets PqsR, thus providing a proof of concept for this novel antivirulence therapy. 相似文献
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Guida WC Hamilton AD Crotty JW Sebti SM 《Journal of computer-aided molecular design》2005,19(12):871-885
Summary Using MacroModel, peptide, peptidomimetic and non-peptidomimetic inhibitors of the zinc metalloenzyme, farnesyltransferase
(FTase), were docked into the enzyme binding site. Inhibitor flexibility, farnesyl pyrophosphate substrate flexibility, and
partial protein flexibility were taken into account in these docking studies. In addition to CVFM and CVIM, as well as our
own inhibitors FTI-276 and FTI-2148, we have docked other farnesyltransferase inhibitors (FTIs) including Zarnestra, which
presently is in advanced clinical trials. The AMBER* force field was employed, augmented with parameters that were derived
for zinc. A single binding site model that was derived from the crystal structure of CVFM complexed with farnesyltransferase
and farnesylpyrophosphate was used for these studies. The docking results using the lowest energy structure from the simulation,
or one of the lowest energy structures, were generally in excellent agreement with the X-ray structures. One of the most important
findings of this study is that numerous alternative conformations for the methionine side chain can be accommodated by the
enzyme suggesting that the methionine pocket can tolerate groups larger than methionine at the C-terminus of the tetrapeptide
and suggesting alternative locations for the placement of side chains that may improve potency. 相似文献
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Multivalent Inhibitors for Carbohydrate‐Processing Enzymes: Beyond the “Lock‐and‐Key” Concept 下载免费PDF全文
Dr. Sébastien G. Gouin 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(37):11616-11628
During the last decades, tremendous chemical efforts have been dedicated to design monovalent inhibitors of carbohydrate‐processing enzymes, with comparatively few rewards in terms of marketed drugs. Recently, an alternative to the traditional “lock and key” approach has emerged. Multivalency, a widely used strategy for lectin inhibition, has been successfully applied to specific glycosidases and glycosyltransferases. 相似文献