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https://www.readbyqxmd.com/read/29352107/mycolyltransferase-from-mycobacterium-tuberculosis-in-covalent-complex-with-tetrahydrolipstatin-provides-insights-into-antigen-85-catalysis
#1
Christopher M Goins, Steven Dajnowicz, Micholas D Smith, Jerry M Parks, Donald R Ronning
Mycobacterium tuberculosis Antigen 85 enzymes (Ag85s) catalyze the transfer of mycolic acid (MA) from trehalose monomycolate to produce the mycolyl arabinogalactan (mAG) or trehalose dimycolate (TDM). These lipids define the protective mycomembrane of Mycobacteria. The current model of substrate binding within the active sites of Ag85s for the production of TDM is not sterically and geometrically feasible; additionally, this model does not account for the production of mAG. Furthermore, this model does not address how Ag85s limit the hydrolysis of the acyl-enzyme intermediate while catalyzing acyl transfer...
January 19, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29352069/identification-of-ketene-reactive-intermediate-of-erlotinib-possibly-responsible-for-inactivation-of-p450-enzymes
#2
Huimin Zhao, Siyuan Li, Zixin Yang, Ying Peng, Xiaohui Chen, Jiang Zheng
Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of non-small-cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of CYPs 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29348071/a-focused-fragment-library-targeting-the-antibiotic-resistance-enzyme-oxacillinase-48-synthesis-structural-evaluation-and-inhibitor-design
#3
Sundus Akhter, Bjarte Aarmo Lund, Aya Ismael, Manuel Langer, Johan Isaksson, Tony Christopeit, Hanna-Kirsti S Leiros, Annette Bayer
β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae...
December 30, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29346283/the-biological-role-of-hyaluronan-rich-oocyte-cumulus-extracellular-matrix-in-female-reproduction
#4
REVIEW
Eva Nagyova
Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte. This review focuses on key molecules that play an important role in the formation of the cumulus ECM, generated by the oocyte-cumulus complex. In particular, the specific inhibitors (AG1478, lapatinib, indomethacin and MG132) and progesterone receptor antagonist (RU486) exerting their effects through the remodeling of the ECM of the cumulus cells surrounding the oocyte have been described...
January 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29342125/induction-of-pro-apoptotic-endoplasmic-reticulum-stress-in-multiple-myeloma-cells-by-neo214-perillyl-alcohol-conjugated-to-rolipram
#5
Thomas C Chen, Nymph Chan, Shirin Labib, Jiali Yu, Hee-Yeon Cho, Florence M Hofman, Axel H Schönthal
Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination...
January 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29341591/the-development-of-benzimidazole-based-clickable-probes-for-the-efficient-labeling-of-cellular-protein-arginine-deiminases-pads
#6
Venkatesh J Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J Salinger, Aaron J Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R Thompson
Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets...
January 17, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29337418/specific-non-covalent-interactions-determine-optimal-structure-of-a-buried-ligand-moiety-qm-mm-and-pure-qm-modeling-of-complexes-of-the-small-molecule-cd4-mimetics-and-hiv1-gp120
#7
Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams
The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120...
January 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29337202/progress-with-covalent-small-molecule-kinase-inhibitors
#8
REVIEW
Zheng Zhao, Philip E Bourne
With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens of structural system pharmacology, here we review this rapid progress by considering design strategies and the challenges and opportunities offered by current CSKIs.
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29326078/ncp7-targeting-a-multitask-protein-for-next-generation-anti-hiv-drug-development-part-2-noncovalent-inhibitors-and-nucleic-acid-binders
#9
REVIEW
Nunzio Iraci, Oriana Tabarrini, Claudio Santi, Luca Sancineto
Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies...
January 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29323872/glycodendrimer-nanocarriers-for-direct-delivery-of-fludarabine-triphosphate-to-leukaemic-cells-improved-pharmacokinetics-and-pharmacodynamics-of-fludarabine
#10
Micha Gorzkiewicz, Izabela Jatczak-Pawlik, Maciej Studzian, Łukasz Pułaski, Dietmar Appelhans, Brigitte Voit, Barbara Klajnert-Maculewicz
Fludarabine, a nucleoside analogue antimetabolite, has complicated pharmacokinetics requiring facilitated transmembrane transport and intracellular conversion to triphosphate nucleotide form (Ara-FATP), causing it to be susceptible to emergence of drug resistance. We are testing a promising strategy to improve its clinical efficacy by direct delivery of Ara-FATP utilizing a biocompatible glycodendrimer nanocarrier system. Here, we present results of a proof-of-concept experiment in several in vitro-cultured leukaemic cell lines (CCRF, THP-1, U937) using non-covalent complexes of maltose-modified poly(propylene imine) dendrimer and fludarabine triphosphate...
January 11, 2018: Biomacromolecules
https://www.readbyqxmd.com/read/29320178/novel-k-ras-g12c-switch-ii-covalent-binders-destabilize-ras-and-accelerate-nucleotide-exchange
#11
Chimno Ihuoma Nnadi, Meredith L Jenkins, Daniel R Gentile, Leslie A Bateman, Daniel Zaidman, Trent E Balius, Daniel K Nomura, John E Burke, Kevan M Shokat, Nir London
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening, against the highly dynamic target K-RasG12C. While the overall hit-rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C...
January 10, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29318298/chlorocarbonylsulfenyl-chloride-cyclizations-towards-piperidin-3-yl-oxathiazol-2-ones-as-potential-covalent-inhibitors-of-threonine-proteases
#12
Marko Jukič, Katarina Grabrijan, Selmir Kadić, Fernando Juan de Lera Garrido, Izidor Sosič, Stanislav Gobec, Aleš Obreza
Using rescaffolding approach, we designed piperidine compounds decorated with an electrophilic oxathiazol-2-one moiety that is known to confer selectivity towards threonine proteases. Our efforts to prepare products according to the published procedures were not successful. Furthermore we identified major side products containing nitrile functional group, resulting from carboxamide dehydration. We systematically optimized reaction conditions towards our desired products to identify heating of carboxamides with chlorocarbonylsulfenyl chloride and sodium carbonate as base in dioxane at 100 °C...
December 2017: Acta Chimica Slovenica
https://www.readbyqxmd.com/read/29313673/epoxycyclohexenedione-type-compounds-are-a-new-class-of-inhibitors-of-the-bovine-mitochondrial-adp-atp-carrier
#13
Ayaki Aoyama, Masatoshi Murai, Naoya Ichimaru, Shunsuke Aburaya, Wataru Aoki, Hideto Miyoshi
Through the extensive screening of our chemical library, we found epoxycyclohexenedione (ECHD)-type compounds (AMM-59 and -120) as unique inhibitors of the bovine heart mitochondrial ADP/ATP carrier (AAC). The present study investigated the mechanism of the inhibition of AAC by ECHDs using submitochondrial particles (SMPs). Proteomic analyses of ECHD-bound AAC as well as biochemical characterization using different SH-reagents showed that ECHDs inhibit the function of AAC by covalently binding primarily to Cys57 and secondarily to Cys160...
January 9, 2018: Biochemistry
https://www.readbyqxmd.com/read/29313669/design-of-small-molecules-that-compete-with-nucleotide-binding-to-an-engineered-oncogenic-kras-allele
#14
Yan Zhang, Mare-Helene Larraufie, Leila Musavi, Hemanth Akkiraju, Lewis M Brown, Brent R Stockwell
RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult due to the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS, and a covalent inhibitor that competes for GTP and GDP. This ligand-receptor combination demonstrates that the high affinity of GTP/GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site...
January 9, 2018: Biochemistry
https://www.readbyqxmd.com/read/29306437/covalent-probes-for-carbohydrate-active-enzymes-from-glycosidases-to-glycosyltransferases
#15
Yong Xu, Najib Uddin, Gerd K Wagner
Covalent probes for glycosidases and glycosyltransferases are of great interest as tool compounds for chemical biology. For glycosidases, a sizable number of such probes have been developed from covalent glycosidase inhibitors. We review selected recent examples and highlight different design strategies, including probes based on photoaffinity labels and mechanism-based inhibitors, as well as their applications in biology and for activity-based protein profiling. In contrast to glycosidases, only a limited number of covalent probes have been reported to date for glycosyltransferases...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29306436/activity-based-probes-for-glycosidases-profiling-and-other-applications
#16
Chi-Lin Kuo, Eline van Meel, Kassiani Kytidou, Wouter Willem Kallemeijn, Martin Witte, Herman Stephen Overkleeft, Marta Elena Artola, Johannes Maria Aerts
Glycosidases mediate the fragmentation of glycoconjugates in the body, including the vital recycling of endogenous molecules. Several inherited diseases in man concern deficiencies in lysosomal glycosidases degrading glycosphingolipids. Prominent is Gaucher disease caused by an impaired lysosomal β-glucosidase (glucocerebrosidase, GBA) and resulting in pathological lysosomal storage of glucosylceramide (glucocerebroside) in tissue macrophages. GBA is a retaining glucosidase with a characteristic glycosyl-enzyme intermediate formed during catalysis...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29305884/aminoacyl-trna-synthetases-structure-function-and-drug-discovery
#17
REVIEW
Vijayakumar Rajendran, Parismita Kalita, Harish Shukla, Awanish Kumar, Timir Tripathi
Aminoacyl-tRNA synthetases (AARSs) are the enzymes that catalyze the aminoacylation reaction by covalently linking an amino acid to its cognate tRNA in the first step of protein translation. Beyond this classical function, these enzymes are also known to have a role in several metabolic and signaling pathways that are important for cell viability. Study of these enzymes is of great interest to the researchers due to its pivotal role in the growth and survival of an organism. Further, unfolding the interesting structural and functional aspects of these enzymes in the last few years has qualified them as a potential drug target against various diseases...
January 3, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29305052/progress-curve-analysis-of-the-kinetics-of-slow-binding-anticancer-drug-inhibitors-of-the-20s-proteasome
#18
Brian B Hasinoff
Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Carfilzomib and oprozomib are epoxyketones that form an irreversible covalent bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. The binding kinetics of some of these drugs have either not been well characterized, or have been studied under a variety of different conditions. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome was determined under a standard set of conditions in order to compare the kinetic and equilibrium properties of these drugs...
January 2, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29301937/cyclipostins-and-cyclophostin-analogs-inhibit-the-antigen-85c-from-mycobacterium-tuberculosis-both-in-vitro-and-in-vivo
#19
Albertus Viljoen, Matthias Richard, Phuong Chi Nguyen, Patrick Fourquet, Luc Camoin, Rishi R Paudal, Giri R Gnawali, Christopher D Spilling, Jean-François Cavalier, Stéphane Canaan, Mickael Blaise, Laurent Kremer
An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of Cyclipostins and Cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29301501/inhibition-of-neddylation-facilitates-cell-migration-through-enhanced-phosphorylation-of-caveolin-1-in-pc3-and-u373mg-cells
#20
Sung Yeon Park, Jong-Wan Park, Gun-Woo Lee, Lan Li, Yang-Sook Chun
BACKGROUND: Protein neddylation is a post-translational modification by a covalent conjugation with the neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Although this process has been reported to participate in diverse cellular signaling, little is known about its role in cancer cell migration. Given a recent proteomics report showing that NEDD8 is downregulated in prostate cancer tissues versus normal prostate tissues, we tested the possibility that neddylation plays a role in cancer evolution, and then tried to identify target proteins of the neddylation...
January 5, 2018: BMC Cancer
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