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Covalent inhibitors

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https://www.readbyqxmd.com/read/28820941/a-photoactivatable-probe-for-super-resolution-imaging-of-enzymatic-activity-in-live-cells
#1
Elias A Halabi, Zacharias Thiel, Nils Trapp, Dorothea Pinotsi, Pablo Rivera-Fuentes
A dual-activatable, fluorogenic probe was developed to sense esterase activity with single-molecule resolution. Without enzymatic pre-activation, the diazoindanone-based probe has an electron poor core and, upon irradiation, undergoes Wolff rearrangement to give a ring-expanded xanthene core that is non-emissive. If the probe is pre-activated by carboxylesterases, the tricyclic core becomes electron-rich and the photoinduced Wolff rearrangement produces a highly emissive rhodol dye. Live-cell and solution studies confirmed the selectivity of the probe and revealed that the photoactivated dye does not diffuse away from the original location of activation because the intermediate ketene forms a covalent bond with surrounding macromolecules...
August 18, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28818459/a-novel-delocalized-lipophilic-cation-chlorambucil-conjugate-inhibits-p-glycoprotein-in-hepg2-adm-cells
#2
Teng Liu, Yongbo Peng, Xiong Li, Lian Liu, Fang Liu, Leye He
Multidrug resistance (MDR) limits the application of a large number of cancer-fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28815420/road-map-for-the-structure-based-design-of-selective-covalent-hcv-ns3-4a-protease-inhibitors
#3
REVIEW
Letitia Shunmugam, Pritika Ramharack, Mahmoud E S Soliman
Over the last 2 decades, covalent inhibitors have gained much popularity and is living up to its reputation as a powerful tool in drug discovery. Covalent inhibitors possess many significant advantages including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent exposed substrate-binding domains. However, rapidly mounting concerns over the potential toxicity, highly reactive nature and general lack of selectivity have negatively impacted covalent inhibitor development...
August 16, 2017: Protein Journal
https://www.readbyqxmd.com/read/28811524/synthesis-of-sulfo-sialic-acid-analogues-potent-neuraminidase-inhibitors-in-regards-to-anomeric-functionality
#4
Christopher J Vavricka, Chiaki Muto, Tomohisa Hasunuma, Yoshinobu Kimura, Michihiro Araki, Yan Wu, George F Gao, Hiroshi Ohrui, Minoru Izumi, Hiromasa Kiyota
The design, synthesis and application of N-acetylneuraminic acid-derived compounds bearing anomeric sulfo functional groups are described. These novel compounds, which we refer to as sulfo-sialic acid analogues, include 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid and its 4-deoxy-3,4-dehydrogenated pseudoglycal. While 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid contains no further modifications of the 2-deoxy-pyranose ring, it is still a more potent inhibitor of avian-origin H5N1 neuraminidase (NA) and drug-resistant His275Tyr NA as compared to the oxocarbenium ion transition state analogue 2,3-dehydro-2-deoxy-N-acetylneuraminic acid...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805040/hpma-copolymer-drug-conjugates-with-controlled-tumor-specific-drug-release
#5
REVIEW
Petr Chytil, Eva Koziolová, Tomáš Etrych, Karel Ulbrich
Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose...
August 14, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28800957/insight-into-the-mode-of-action-and-selectivity-of-pbrm-a-covalent-steroidal-inhibitor-of-17%C3%AE-hydroxysteroid-dehydrogenase-type-1
#6
Alexandre Trottier, René Maltais, Diana Ayan, Xavier Barbeau, Jenny Roy, Martin Perreault, Richard Poulin, Patrick Lagüe, Donald Poirier
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17β-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated...
August 8, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28799332/attaching-the-nora-efflux-pump-inhibitor-inf55-to-methylene-blue-enhances-antimicrobial-photodynamic-inactivation-of-methicillin-resistant-staphylococcus-aureus-in-vitro-and-in-vivo
#7
Ardeshir Rineh, Naveen K Dolla, Anthony R Ball, Maria Magana, John B Bremner, Michael R Hamblin, George P Tegos, Michael J Kelso
Antimicrobial photodynamic inactivation (aPDI) uses photosensitizers (PSs) and harmless visible light to generate reactive oxygen species (ROS) and kill microbes. Multidrug efflux systems can moderate the phototoxic effects of PSs by expelling the compounds from cells. We hypothesized that increasing intracellular concentrations of PSs by inhibiting efflux with a covalently attached efflux pump inhibitor (EPI) would enhance bacterial cell phototoxicity and reduce exposure of neighboring host cells to damaging ROS...
August 17, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28795598/inhibition-studies-of-dna-methyltransferases-by-maleimide-derivatives-of-rg108-as-non-nucleoside-inhibitors
#8
Grégoire Rondelet, Laurence Fleury, Céline Faux, Véronique Masson, Jean Dubois, Paola B Arimondo, Luc Willems, Johan Wouters
AIM: DNA methyltransferases (DNMTs) are important drug targets for epigenetic therapy of cancer. Nowadays, non-nucleoside DNMT inhibitors are in development to address high toxicity of nucleoside analogs. However, these compounds still have low activity in cancer cells and mode of action of these compounds remains unclear. MATERIALS & METHODS: In this work, we studied maleimide derivatives of RG108 by biochemical, structural and computational approaches to highlight their inhibition mechanism on DNMTs...
August 10, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28795372/development-of-a-pharmacophore-for-cruzain-using-oxadiazoles-as-virtual-molecular-probes-quantitative-structure-activity-relationship-studies
#9
Anacleto S de Souza, Marcelo T de Oliveira, Adriano D Andricopulo
Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0...
August 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28781124/potent-and-selective-covalent-quinazoline-inhibitors-of-kras-g12c
#10
Mei Zeng, Jia Lu, Lianbo Li, Frederic Feru, Chunshan Quan, Thomas W Gero, Scott B Ficarro, Yuan Xiong, Chiara Ambrogio, Raymond M Paranal, Marco Catalano, Jay Shao, Kwok-Kin Wong, Jarrod A Marto, Eric S Fischer, Pasi A Jänne, David A Scott, Kenneth D Westover, Nathanael S Gray
Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C...
August 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781083/kras-g12c-drug-development-discrimination-between-switch-ii-pocket-configurations-using-hydrogen-deuterium-exchange-mass-spectrometry
#11
Jia Lu, Rane A Harrison, Lianbo Li, Mei Zeng, Sudershan Gondi, David Scott, Nathanael S Gray, John R Engen, Kenneth D Westover
KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders...
July 25, 2017: Structure
https://www.readbyqxmd.com/read/28776779/a-multilevel-theoretical-study-to-disclose-the-binding-mechanisms-of-gold-iii-bipyridyl-compounds-as-selective-aquaglyceroporin-inhibitors
#12
Valentina Graziani, Alessandro Marrone, Nazzareno Re, Cecilia Coletti, James A Platts, Angela Casini
Structural studies have paved the avenue to a deep understanding of AQPs, small ancient proteins providing efficient transmembrane pathways for water, small uncharged solutes as glycerol, and possibly gas molecules. Despite the numerous studies, their roles in health and disease remain to be fully disclosed. The recent discovery of Au(III) complexes as potent and selective inhibitors of aquaglyceroporins isoforms paves the way to their possible therapeutic application. The binding of the selective human AQP3 inhibitor, the cationic complex [Au(bipy)Cl2]+ (Aubipy), with the protein channel was investigated here by means of a multilevel theoretical workflow including QM, MD, and QM/MM approaches...
August 4, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28776021/1-6-cyclophellitol-cyclosulfates-a-new-class-of-irreversible-glycosidase-inhibitor
#13
Marta Artola, Liang Wu, Maria J Ferraz, Chi-Lin Kuo, Lluís Raich, Imogen Z Breen, Wendy A Offen, Jeroen D C Codée, Gijsbert A van der Marel, Carme Rovira, Johannes M F G Aerts, Gideon J Davies, Herman S Overkleeft
The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors...
July 26, 2017: ACS Central Science
https://www.readbyqxmd.com/read/28758655/inhibitors-of-nicotinamide-n-methyltransferase-designed-to-mimic-the-methylation-reaction-transition-state
#14
Matthijs J van Haren, Rebecca Taig, Jilles Kuppens, Javier Sastre Toraño, Ed E Moret, Richard B Parsons, Davide Sartini, Monica Emanuelli, Nathaniel I Martin
Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyses the methylation of nicotinamide to form N'-methylnicotinamide. Both NNMT and its methylated product have recently been linked to a variety of diseases, suggesting a role for the enzyme as a therapeutic target beyond its previously ascribed metabolic function in detoxification. We here describe the systematic development of NNMT inhibitors derived from the structures of the substrates involved in the methylation reaction. By covalently linking fragments of the NNMT substrates a diverse library of bisubstrate-like compounds was prepared...
August 9, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28754930/the-versatility-of-boron-in-biological-target-engagement
#15
REVIEW
Diego B Diaz, Andrei K Yudin
Boron-containing molecules have been extensively used for the purposes of chemical sensing, biological probe development and drug discovery. Due to boron's empty p orbital, it can coordinate to heteroatoms such as oxygen and nitrogen. This reversible covalent mode of interaction has led to the use of boron as bait for nucleophilic residues in disease-associated proteins, culminating in the approval of new therapeutics that work by covalent mechanisms. Our analysis of a wide range of covalent inhibitors with electrophilic groups suggests that boron is a unique electrophile in its chameleonic ability to engage protein targets...
July 25, 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28744747/structural-and-inhibition-analysis-of-novel-sulfur-rich-2-mercaptobenzothiazole-and-1-2-3-triazole-ligands-against-mycobacterium-tuberculosis-dpre1-enzyme
#16
Sumita Karan, Vipin K Kashyap, Syed Shafi, Ajay K Saxena
Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose oxidase (MtbDprE1) acts in concert with decaprenylphosphoryl-β-D-ribose 2-epimerase (MtbDprE2) and catalyzes the epimerization of DPR into DPA. DPA is the sole precursor for synthesis of arabinogalactan and lipoarabinomannan in the mycobacterial cell wall. MtbDprE1 is a unique antimalarial drug target and many covalent and non-covalent inhibitors against MtbDprE1 have been studied for their antituberculosis activities. In the current study, we have purified MtbDprE1 enzyme and synthesized six sulfur-rich 2-mercaptobenzothiazole and 1, 2, 3-triazole conjugated ligands and performed binding analysis with MtbDprE1...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28743742/disease-causing-mutations-in-the-serpin-antithrombin-reveal-a-key-domain-critical-for-inhibiting-protease-activities
#17
Sonia Águila, Gonzalo Izaguirre, Irene Martinez-Martinez, Vicente Vicente, Steven T Olson, Javier Corral
Antithrombin mainly inhibits factor Xa, and thrombin. The reactive center loop (RCL) is crucial for its interactions with its protease targets and is fully inserted into the A-sheet after its cleavage, causing translocation of the covalently linked protease to the opposite end of the A-sheet. Antithrombin variants with altered RCL hinge residues behave as substrates rather than inhibitors, resulting in stoichiometries of inhibition greater than one. Other antithrombin residues have been suggested to interfere with RCL insertion or the stability of the antithrombin-protease complex, but available crystal structures or mutagenesis studies have failed to identify such residues...
July 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28739781/structural-insights-into-the-tla-3-extended-spectrum-%C3%AE-lactamase-and-its-inhibition-by-avibactam-and-op0595
#18
Wanchun Jin, Jun-Ichi Wachino, Yoshihiro Yamaguchi, Kouji Kimura, Anupriya Kumar, Mototsugu Yamada, Akihiro Morinaka, Yoshiaki Sakamaki, Minoru Yonezawa, Hiromasa Kurosaki, Yoshichika Arakawa
Development of effective inhibitors that block extended-spectrum β-lactamases (ESBLs) and restore the action of β-lactams represents an effective strategy against ESBL-producing Enterobacteriaceae We evaluated the inhibitory effect of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent Ki app of 1.71 ± 0.10 and 1.49 ± 0.05 μM, respectively, and could restore susceptibility to cephalosporins in TLA-3-producing Escherichia coli The acylation rate constant [k2/K, (3...
July 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28735002/immobilization-of-%C3%AE-galactosidase-on-surface-modified-cobalt-multiwalled-carbon-nanotube-nanocomposite-improves-enzyme-stability-and-resistance-to-inhibitor
#19
Maryam Khan, Qayyum Husain, Rani Bushra
The present study aimed to work out a high yield procedure for immobilization of Aspergillus oryzae β-galactosidase on polyaniline cobalt multiwalled carbon nanotubes nanocomposite (PANI/Co/MWCNTNC) by physical adsorption and covalent attachment via glutaraldehyde. The binding was confirmed by scanning and transmission electron microscopy along with Fourier transform-infrared spectroscopy. The immobilization yields obtained for adsorbed and cross-linked enzymes were 93% and 97%, respectively. The covalently immobilized enzyme was remarkably more stable at extremes of pH and temperature compared to native and adsorbed enzymes...
July 19, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28732309/zebularine-induces-replication-dependent-double-strand-breaks-which-are-preferentially-repaired-by-homologous-recombination
#20
Manuel Luis Orta, Nuria Pastor, Estefanía Burgos-Morón, Inmaculada Domínguez, José Manuel Calderón-Montaño, Carlos Huertas Castaño, Miguel López-Lázaro, Thomas Helleday, Santiago Mateos
Zebularine is a second-generation, highly stable hydrophilic inhibitor of DNA methylation with oral bioavailability that preferentially target cancer cells. It acts primarily as a trap for DNA methyl transferases (DNMTs) protein by forming covalent complexes between DNMT protein and zebularine-substrate DNA. It's well documented that replication-blocking DNA lesions can cause replication fork collapse and thereby to the formation of DNA double-strand breaks (DSB). DSB are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death...
July 12, 2017: DNA Repair
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