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Covalent inhibitors

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https://www.readbyqxmd.com/read/28337328/structure-activity-relationship-study-of-ql47-a-broad-spectrum-antiviral-agent
#1
Yanke Liang, Melissanne de Wispelaere, Margot Carocci, Qingsong Liu, Jinhua Wang, Priscilla L Yang, Nathanael S Gray
Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28336347/solution-conformations-of-a-linked-construct-of-the-zika-virus-ns2b-ns3-protease
#2
Mithun C Mahawaththa, Benjamin J G Pearce, Bim Graham, Christian D Klein, Christoph Nitsche, Gottfried Otting
The Zika virus presents a serious risk for global health. Crystal structures of different constructs of the Zika virus NS2B-NS3 protease (NS2B-NS3pro) have been determined with the aim to provide a basis for rational drug discovery. In these structures, the C-terminal β-hairpin of NS2B, NS2Bc, was observed to be either disordered (open conformation) or bound to NS3pro complementing the substrate binding site (closed conformation). Enzymatically active constructs of flaviviral NS2B-NS3 proteases commonly used for inhibitor testing contain a covalent peptide linker between NS2B and NS3pro...
March 20, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28333400/an-improved-model-of-the-trypanosoma-brucei-ctp-synthetase-glutaminase-domain-acivicin-complex
#3
Juliana Oliveira de Souza, Alice Dawson, William Nigel Hunter
The natural product acivicin inhibits the glutaminase activity of CTP synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1 Å resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the Protein Data Bank and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28330993/transition-state-mimics-are-valuable-mechanistic-probes-for-structural-studies-with-the-arginine-methyltransferase-carm1
#4
Matthijs J van Haren, Nils Marechal, Nathalie Troffer-Charlier, Agostino Cianciulli, Gianluca Sbardella, Jean Cavarelli, Nathaniel I Martin
Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics...
March 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28326775/determining-cysteines-available-for-covalent-inhibition-across-the-human-kinome
#5
Zheng Zhao, Qingsong Liu, Spencer Bliven, Lei Xie, Philip E Bourne
Covalently bound protein kinase inhibitors have been frequently designed to target non-catalytic cysteines at the ATP binding site. Thus, it is important to know if a given cysteine can form a covalent bond. Here we combine a function-site interaction fingerprint method and DFT calculations to determine the potential of cysteines to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site cysteine dataset was assembled. The orientation of the cysteine thiol group indicates which cysteines can potentially form covalent bonds...
March 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28325837/threonine-eliminylation-by-bacterial-phosphothreonine-lyases-rapidly-causes-crosslinking-of-mapk-in-live-cells
#6
Benoit M Meijer, Suk Min Jang, Ida C Guerrera, Cerina Chhuon, Joanna Lipecka, Caroline Reisacher, Françoise Baleux, Philippe Sansonetti, Christian Muchardt, Laurence Arbibe
Old long-lived proteins contain dehydroalanine (Dha) and dehydrobutyrine (Dhb), two amino acids engendered by dehydration of serines and threonines respectively. While these residues have a suspected role in protein crosslink and aggregation, their direct implication has yet to be determined. Here, we have taken advantage of the ability of the enteropathogen Shigella to convert the phosphothreonine residue of the pT-X-pY consensus sequence of ERK and p38 into Dhb, and followed the impact of dehydration on the fate of the two MAPKs...
March 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28320739/a-covalently-bound-inhibitor-triggers-ezh2-degradation-through-chip-mediated-ubiquitination
#7
Xu Wang, Wei Cao, Jianjun Zhang, Ming Yan, Qin Xu, Xiangbing Wu, Lixin Wan, Zhiyuan Zhang, Chenping Zhang, Xing Qin, Meng Xiao, Dongxia Ye, Yuyang Liu, Zeguang Han, Shaomeng Wang, Li Mao, Wenyi Wei, Wantao Chen
Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2- and methyltransferase-independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2-targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2-SET domain, triggering EZH2 degradation through COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination...
March 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28320299/effects-of-seeding-on-lysozyme-amyloid-fibrillation-in-the-presence-of-epigallocatechin-and-polyethylene-glycol
#8
Li-Xiu Kong, Cheng-Ming Zeng
Preformed amyloid fibrils can act as seeds for accelerating protein fibrillation. In the present study, we examined the effects of preformed seeds on lysozyme amyloid fibrillation in the presence of two distinct inhibitors - epigallocatechin (EGC) and polyethylene glycol 2000 (PEG). The results demonstrated that the effects of fibrillar seeds on the acceleration of lysozyme fibrillation depended on the aggregation pathway directed by an inhibitor. EGC inhibited lysozyme fibrillation and modified the peptide chains with quinone moieties in a concentration-dependent manner...
February 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28287083/brigatinib-combined-with-anti-egfr-antibody-overcomes-osimertinib-resistance-in-egfr-mutated-non-small-cell-lung-cancer
#9
Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28286128/deacylation-mechanism-by-sirt2-revealed-in-the-1-sh-2-o-myristoyl-intermediate-structure
#10
Yi Wang, Yi Man Eva Fung, Weizhe Zhang, Bin He, Matthew Wai Heng Chung, Jing Jin, Jing Hu, Hening Lin, Quan Hao
Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28285521/exploring-covalent-allosteric-inhibition-of-antigen-85c-from-mycobacterium-tuberculosis-by-ebselen-derivatives
#11
Christopher M Goins, Steven J Dajnowicz, Sandeep Thanna, Steven J Sucheck, Jerry Matthew Parks, Donald R Ronning
Previous studies identified ebselen as a potent in vitro and in vivo inhibitor of the Mycobacterium tuberculosis (Mtb) antigen 85 (Ag85) complex, comprising three homologous enzymes required for the biosynthesis of the mycobacterial cell wall. In this study, the Mtb Ag85C enzyme was co-crystallized with azido and adamantyl ebselen derivatives, resulting in two crystallographic structures of 2.01 and 1.30 Å resolution, respectively. Both structures displayed the anticipated covalent modification of the solvent accessible, non-catalytic Cys209 residue forming a selenenylsulfide bond...
March 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28282122/discovery-of-r-1-3-4-amino-3-3-chloro-4-pyridin-2-ylmethoxy-phenyl-1h-pyrazolo-3-4-d-pyrimidin-1-yl-piperidin-1-yl-prop-2-en-1-one-chmfl-egfr-202-as-a-novel-irreversible-egfr-mutants-kinase-inhibitor-with-a-distinct-binding-mode
#12
Aoli Wang, Xixiang Li, Hong Wu, Fengming Zou, Xiao-E Yan, Cheng Chen, Chen Hu, Kailin Yu, Wenchao Wang, Peng Zhao, Jiaxin Wu, Ziping Qi, Wei Wang, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Jing Liu, Qingsong Liu
Based on Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered a novel EGFR inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02), especially it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-Helix-out" inactive EGFR conformation...
March 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28272868/mechanism-based-inhibition-of-the-mycobacterium-tuberculosis-branched-chain-aminotransferase-by-d-and-l-cycloserine
#13
Tathyana Mar Amorim Franco, Lorenza Favrot, Olivia Vergnolle, John S Blanchard
The branched-chain aminotransferase is a pyridoxal 5'-phosphate (PLP)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, L-leucine, L-isoleucine and L-valine, in bacteria. We have investigated the mechanism of inactivation of the branched-chain aminotransferase from Mycobacterium tuberculosis (MtIlvE) by D- and L-cycloserine. D-cycloserine is currently used only in the treatment of multidrug-drug resistant tuberculosis. Our results show a time- and concentration-dependent inactivation of MtIlvE by both isomers, with L-cycloserine being a 40-fold better inhibitor of the enzyme...
March 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28271476/%C3%AE-2-macroglobulins-structure-and-function
#14
Irene Garcia-Ferrer, Aniebrys Marrero, F Xavier Gomis-Rüth, Theodoros Goulas
α2-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the "Venus flytrap" and the "snap-trap" mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of α2-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment. In some homologs, a second action takes place that involves a highly reactive β-cysteinyl-γ-glutamyl thioester bond, which covalently binds cleaving peptidases and thus contributes to the further stabilization of the enzyme:inhibitor complex...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28267172/discovery-of-a-new-class-of-highly-potent-necroptosis-inhibitors-targeting-the-mixed-lineage-kinase-domain-like-protein
#15
Bo Yan, Lei Liu, Shaoqiang Huang, Yan Ren, Huayi Wang, Zhenglin Yao, Lin Li, She Chen, Xiaodong Wang, Zhiyuan Zhang
We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target...
March 7, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28253433/ubfluor-a-fluorescent-thioester-to-monitor-hect-e3-ligase-catalysis
#16
David T Krist, Peter K Foote, Alexander V Statsyuk
HECT E3 ubiquitin ligases (∼28 are known) are associated with many phenotypes in eukaryotes and are important drug targets. However, assays used to screen for small molecule inhibitors of HECT E3s are complex and require ATP, Ub, E1, E2, and HECT E3 enzymes, producing three covalent thioester enzyme intermediates E1∼Ub, E2∼Ub, and HECT E3∼Ub (where ∼ indicates a thioester bond), and mixtures of polyubiquitin chains. To reduce the complexity of the assay, we developed a novel class of fluorescent probes, UbFluor, that act as mechanistically relevant pseudosubstrates of HECT E3s...
March 2, 2017: Current Protocols in Chemical Biology
https://www.readbyqxmd.com/read/28253193/structural-and-functional-insight-into-pan-endopeptidase-inhibition-by-%C3%AE-2-macroglobulins
#17
Theodoros Goulas, Irene Garcia-Ferrer, Aniebrys Marrero, Laura Marino-Puertas, Stephane Duquerroy, F Xavier Gomis-Rüth
Peptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites...
March 2, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28242208/interplay-between-sirt1-and-hepatitis-b-virus-x-protein-in-the-activation-of-viral-transcription
#18
Jian-Jun Deng, Ka-Yiu Edwin Kong, Wei-Wei Gao, Hei-Man Vincent Tang, Vidyanath Chaudhary, Yun Cheng, Jie Zhou, Chi-Ping Chan, Danny Ka-Ho Wong, Man-Fung Yuen, Dong-Yan Jin
Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD(+)-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription...
February 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28240180/structure-based-virtual-screening-approaches-in-kinase-directed-drug-discovery
#19
Dávid Bajusz, György G Ferenczy, György M Keserű
Protein kinases are one of the most targeted protein families in current drug discovery pipelines. They are implicated in many oncological, inflammatory, CNS-related and other clinical indications. Virtual screening is a computational technique with a diverse set of available tools that has been shown many times to provide novel starting points for kinase-directed drug discovery. This review starts with a concise overview of the function, structural features and inhibitory mechanisms of protein kinases. In addition to briefly reviewing practical aspects of structure-based virtual screenings, we discuss several case studies to illustrate the state of the art in the virtual screening for type I, type II, allosteric (type III-V) and covalent (type VI) kinase inhibitors...
February 24, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28237762/synthesis-sar-and-molecular-docking-study-of-novel-non-%C3%AE-lactam-inhibitors-of-tem-type-%C3%AE-lactamase
#20
Roman L Antipin, Daria A Beshnova, Rostislav A Petrov, Anna S Shiryaeva, Irina P Andreeva, Vitaly G Grigorenko, Maya Yu Rubtsova, Alexander G Majouga, Victor S Lamzin, Alexey M Egorov
The novel classes of acylated phenoxyanilide and thiourea compounds were investigated for their ability to inhibit TEM type β-lactamase enzyme. Two compounds 4g and 5c reveal the inhibition potency in micromolar range and show their action by non-covalent binding in the vicinity of the TEM-171 active site. The structure activity relationship around carbon chain length and different substituents in ortho- and para-positions of acylated phenoxyanilide as well as molecular modelling study has been performed.
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
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