共查询到20条相似文献,搜索用时 15 毫秒
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Federica Mancini Dr. M. Yagiz Unver Dr. Walid A. M. Elgaher Dr. Varsha R. Jumde Alaa Alhayek Dr. Peer Lukat Dr. Jennifer Herrmann Dr. Martin D. Witte Dr. Matthias Köck Prof. Dr. Wulf Blankenfeldt Prof. Dr. Rolf Müller Prof. Dr. Anna K. H. Hirsch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(64):14585-14593
Kinetic target-guided synthesis represents an efficient hit-identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β-sliding clamp DnaN, respectively. Highly sensitive mass-spectrometry methods enabled monitoring of the protein-templated reaction of four complementary reaction partners, which occurred in a background-free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β-sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target. 相似文献
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Dr. Lech‐Gustav Milroy Dr. Maria Bartel Dr. Morkos A. Henen Dr. Seppe Leysen Joris M. C. Adriaans Prof. Dr. Luc Brunsveld Dr. Isabelle Landrieu Dr. Christian Ottmann 《Angewandte Chemie (International ed. in English)》2015,54(52):15720-15724
The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs. 相似文献
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Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach 下载免费PDF全文
Dr. Maria G. Chini Dr. Nicola Malafronte Dr. Maria C. Vaccaro Dr. Maria J. Gualtieri Dr. Antonio Vassallo Dr. Michele Vasaturo Prof. Sabrina Castellano Dr. Ciro Milite Prof. Antonietta Leone Prof. Giuseppe Bifulco Prof. Nunziatina De Tommasi Prof. Fabrizio Dal Piaz 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(37):13236-13250
The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high‐affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound 1 (cedrelosin A), 3 (7α‐limonylacetate), and 5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90α chaperone activity. Consistent with these findings, the three compounds caused a depletion of c‐Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol‐derivatives as promising scaffolds for the design of novel Hsp90α inhibitors. 相似文献
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Richiro Ushimaru Zhang Chen Houyuan Zhao Po‐hsun Fan Hung‐wen Liu 《Angewandte Chemie (International ed. in English)》2020,59(9):3558-3562
Albomycin δ2 is a sulfur‐containing sideromycin natural product that shows potent antibacterial activity against clinically important pathogens. The l ‐serine‐thioheptose dipeptide partial structure, known as SB‐217452, has been found to be the active seryl‐tRNA synthetase inhibitor component of albomycin δ2. Herein, it is demonstrated that AbmF catalyzes condensation between the 6′‐amino‐4′‐thionucleoside with the d ‐ribo configuration and seryl‐adenylate supplied by the serine adenylation activity of AbmK. Formation of the dipeptide is followed by C3′‐epimerization to produce SB‐217452 with the d ‐xylo configuration, which is catalyzed by the radical S‐adenosyl‐l ‐methionine enzyme AbmJ. Gene deletion suggests that AbmC is involved in peptide assembly linking SB‐217452 with the siderophore moiety. This study establishes how the albomycin biosynthetic machinery generates its antimicrobial component SB‐217452. 相似文献
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A Divalent PAMAM‐Based Matrix Metalloproteinase/Carbonic Anhydrase Inhibitor for the Treatment of Dry Eye Syndrome 下载免费PDF全文
V. Baldoneschi Prof. S. Burgalassi Dr. D. Vullo Dr. A. Akdemir Dr. E. Dragoni A. Louka M. Mamusa Dr. D. Monti Prof. D. Berti Prof. E. Novellino Prof. G. De Rosa Prof. C. T. Supuran Prof. C. Nativi 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(5):1714-1721
Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM‐based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation. 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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Adam Hotra Priya Ragunathan Pearly Shuyi Ng Pattarakiat Seankongsuk Amaravadhi Harikishore Jickky Palmae Sarathy Wuan‐Geok Saw Umayal Lakshmanan Patcharaporn Sae‐Lao Nitin Pal Kalia Joon Shin Revathy Kalyanasundaram Sivaraj Anbarasu Krupakar Parthasarathy Chaudhari Namrata Pradeep Harshyaa Makhija Peter Drge Anders Poulsen Jocelyn Hui Ling Tan Kevin Pethe Thomas Dick Roderick W. Bates Gerhard Grüber 《Angewandte Chemie (International ed. in English)》2020,59(32):13295-13304
The F1FO‐ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium‐specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug‐ as well as bedaquiline‐resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti‐tuberculosis F‐ATP synthase inhibitors. 相似文献
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Design of the First‐in‐Class,Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction 下载免费PDF全文
Dr. Shilin Xu Dr. Angelo Aguilar Dr. Tianfeng Xu Dr. Ke Zheng Dr. Liyue Huang Prof. Dr. Jeanne Stuckey Dr. Krishnapriya Chinnaswamy Dr. Denzil Bernard Dr. Ester Fernández‐Salas Dr. Liu Liu Dr. Mi Wang Donna McEachern Sally Przybranowski Caroline Foster Prof. Dr. Shaomeng Wang 《Angewandte Chemie (International ed. in English)》2018,57(6):1601-1605
The structure‐based design of M‐525 as the first‐in‐class, highly potent, irreversible small‐molecule inhibitor of the menin‐MLL interaction is presented. M‐525 targets cellular menin protein at sub‐nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL‐regulated gene expression in MLL leukemia cells. M‐525 demonstrates high cellular specificity over non‐MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co‐crystal structure of M‐525 in complex with menin firmly establish its mode of action. A single administration of M‐525 effectively suppresses MLL‐regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M‐525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia. 相似文献
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《Angewandte Chemie (International ed. in English)》2017,56(47):14836-14841
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co‐crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug‐like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight‐binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology. 相似文献
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