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51.
Ines Pires da Silva Isabella C. Glitza Lauren E. Haydu Romany Johnpulle Patricia D. Banks George D. Grass Simone M. A. Goldinger Jessica L. Smith Ashlyn S. Everett Peter Koelblinger Rachel Roberts‐Thomson Michael Millward Victoria G. Atkinson Alexander Guminski Rony Kapoor Robert M. Conry Matteo S. Carlino Wei Wang Mark J. Shackleton Zeynep Eroglu Serigne Lo Angela M. Hong Georgina V. Long Douglas B. Johnson Alexander M. Menzies 《Pigment cell & melanoma research》2019,32(4):553-563
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Debnath Bhuniya Rajendra K. Kharul Atul Hajare Nadim Shaikh Sandeep Bhosale Sandip Balwe Fouzia Begum Siddhartha De Sonalee Athavankar Dhananjay Joshi Vamsi Madgula Kaushal Joshi Amol A. Raje Ashwinkumar V. Meru Amol Magdum Kasim A. Mookhtiar Rashmi Barbhaiya 《Bioorganic & medicinal chemistry letters》2019,29(2):238-243
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (?)-12a, (?)-12i, (?)-12l–m. The required (?)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (?)-12l and (?)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30?mg/kg po for 7?days. The effects at 30?mg/kg are comparable to that of PF-04457845 (10?mg/kg) and Tramadol (40?mg/kg). 相似文献
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The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy. 相似文献
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Chandra Dinesh Srivastava Rashmi Gupta Vadakattu V. S. R. Franco Christopher M. M. Paasricha Nishat Saifi Shabnam K. Tuteja Narendra Sharma Anil Kumar 《Plant and Soil》2019,441(1-2):261-281
Plant and Soil - Plant growth promoting bacteria (PGPB) containing 1-aminocyclopropane-1-carboxylate (ACC) deaminase can play an important role in abiotic stress tolerance in plants, particularly... 相似文献
57.
Jia Fan Wenyong Fan Jianzhen Lei Yingying Zhou Hongfei Xu Isha Kapoor Guoqing Zhu Juejin Wang 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):218-229
Pressure overload-induced cardiac hypertrophy occurs in response to chronic blood pressure increase, and dysfunction of CaV1.2 calcium channel involves in cardiac hypertrophic processes by perturbing intracellular calcium concentration ([Ca2+]i) and calcium-dependent signaling. As a carbohydrate-binding protein, galectin-1 (Gal-1) is found to bind with CaV1.2 channel, which regulates vascular CaV1.2 channel functions and blood pressure. However, the potential roles of Gal-1 in cardiac CaV1.2 channel (CaV1.2CM) and cardiomyocyte hypertrophy remain elusive. By whole-cell patch clamp, we find Gal-1 decreases the ICa,L with or without isoproterenol (ISO) application by reducing the channel membrane expression in neonatal rat ventricular myocytes (NRVMs). Moreover, Gal-1 could inhibit the current densities of CaV1.2CM by an alternative exon 9*-dependent manner in heterologously expressed HEK293 cells. Of significance, overexpression of Gal-1 diminishes ISO or KCl-induced [Ca2+]i elevation and attenuates ISO-induced hypertrophy in NRVMs. Mechanistically, Gal-1 decreases the ISO or Bay K8644-induced phosphorylation of intracellular calcium-dependent signaling proteins δCaMKII and HDAC4, and inhibits ISO-triggered translocation of HDAC4 in NRVMs. Pathologically, we observe that the expressions of Gal-1 and CaV1.2E9* channels are synchronously increased in rat hypertrophic cardiomyocytes and hearts. Taken together, our study indicates that Gal-1 reduces the channel membrane expression to inhibit the currents of CaV1.2CM in a splice-variant specific manner, which diminishes [Ca2+]i elevation, and attenuates cardiomyocyte hypertrophy by inhibiting the phosphorylation of δCaMKII and HDAC4. Furthermore, our work suggests that dysregulated Gal-1 and CaV1.2 alternative exon 9* might be attributed to the pathological processes of cardiac hypertrophy, and provides a potential anti-hypertrophic target in the heart. 相似文献
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Tolbert WD Ekstrom JL Mathews II Secrist JA Kapoor P Pegg AE Ealick SE 《Biochemistry》2001,40(32):9484-9494
S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. We have determined the structures of S-adenosylmethionine decarboxylase complexed with the competitive inhibitors methylglyoxal bis(guanylhydrazone) and 4-amidinoindan-1-one-2'-amidinohydrazone as well as the irreversible inhibitors 5'-deoxy-5'-[N-methyl-N-[(2-aminooxy)ethyl]amino]adenosine, 5'-deoxy-5'-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine, and the methyl ester analogue of S-adenosylmethionine. These structures elucidate residues important for substrate binding and show how those residues interact with both covalently and noncovalently bound inhibitors. S-Adenosylmethionine decarboxylase has a four-layer alphabeta betaalpha sandwich fold with residues from both beta-sheets contributing to substrate and inhibitor binding. The side chains of conserved residues Phe7, Phe223, and Glu247 and the backbone carbonyl of Leu65 play important roles in binding and positioning the ligands. The catalytically important residues Cys82, Ser229, and His243 are positioned near the methionyl group of the substrate. One molecule of putrescine per monomer is observed between the two beta-sheets but far away from the active site. The activating effects of putrescine may be due to conformational changes in the enzyme, to electrostatic effects, or both. The adenosyl moiety of the bound ligand is observed in the unusual syn conformation. The five structures reported here provide a framework for interpretation of S-adenosylmethionine decarboxylase inhibition data and suggest strategies for the development of more potent and more specific inhibitors of S-adenosylmethionine decarboxylase. 相似文献
60.
Narwal S Balasubrahmanyam A Sadhna P Kapoor H Lodha ML 《Indian journal of experimental biology》2001,39(6):600-603
An antiviral protein from Bougainvillea xbuttiana leaves induced systemic resistance in host plants N. glutinosa and Cyamopsis tetragonoloba against TMV and SRV, respectively which was reversed by actinomycin D, when applied immediately or shortly after antiviral protein treatment. When the inhibitor was applied to the host plant leaves post inoculation, it was effective if applied upto 4 h after virus infection. It also delayed the expression of symptoms in systemic hosts of TMV. The inhibitor showed characteristic N-glycosidase activity on 25S rRNA of tobacco ribosomes, suggesting that it could also be interfering with virus multiplication through ribosome-inactivation process. 相似文献