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991.
Nisthul A. Amrutha P. Retnakumari Archana Shankar G. Mohan Ruby John Anto C. Sadasivan 《Journal of cellular biochemistry》2019,120(10):16643-16657
For the past few decades, structure-based drug discovery (SBDD) has become an inevitable technique in the drug development process for screening hit compounds against therapeutic targets. Here, we have successfully used the SBDD approach viz. virtual high-throughput screening to identify potential inhibitors against the Ketoacyl synthase (KS) domain of Fatty acid synthase (FASN). Overexpression of FASN, and subsequent enhancement of de novo lipogenesis is a key survival strategy of cancer cells. Hence, targeting lipid metabolism using FASN inhibitors has been considered as a promising method to induce metabolic stress, thereby posing a survival disadvantage to cancer cells. In the present study, we have successfully identified eight FASN inhibitors from Asinex Elite database by implementing in silico tools. Five of the hit compounds share a common ring structure, which enables characteristic binding interactions with FASN-KS. Among them, in vitro validation showed that SFA 22637550 possesses significant FASN inhibitory activity and antiproliferative effect in human cancer cells of various origins. The maximum sensitivity was exhibited towards HepG2 hepatocellular carcinoma cells (IC50 = 28 µM). The mode of cell death was found to be apoptosis with a significant increase in SubG0 population without affecting any other phases of the cell cycle. The current study puts forward an excellent core structure for the development of potent FASN inhibitors for successfully targeting cancer cell metabolism, thereby causing selective cell death. 相似文献
992.
Khyati P. Thakor Miral V. Lunagariya Bhupesh S. Bhatt Mohan N. Patel 《Luminescence》2019,34(1):113-124
Novel palladium(II) complexes ( 7a–7e ) of substituted quinoline derivatives were synthesized. The complexes were characterized using various techniques such as thermogravimetric analysis (TGA), elemental analysis, conductance measurement, mass, absorption, infra‐red (IR), 1H NMR, 13C NMR and energy‐dispersive X‐ray spectroscopy (EDX). Complexes for herring sperm DNA (HS DNA) binding were explored and absorption titration and the binding constant (Kb) as well as Gibb's free energy were evaluated. Complex 7d exhibited the highest binding constant, therefore the thermodynamic parameters of 7d at different temperatures were evaluated. To support the results of the absorption titration, fluorescence titration, viscosity measurement and molecular docking studies were performed. The fluorescence quenching data as evaluated from Stern–Volmer equation were used to calculate KSV, Kf and the number of binding sites. The results of all these studies were in good agreement with the absorption study. DNA electrophoretic mobility was performed to explore the possible application of metal complexes as artificial metallonucleases. The antibacterial activity of the complexes was accessed against different pathogenic bacteria and cytotoxicity was measured using brine shrimp and S. pombe. 相似文献
993.
Ashutosh Singh Sandeep K. Gupta Per Alström Dhananjai Mohan Daniel M. Hooper Ramani S. Kumar Dinesh Bhatt Pratap Singh Trevor D. Price 《Ibis》2020,162(3):924-935
Taxa classified as subspecies may in fact be cryptic species. We assessed the taxonomic status of the Blue-throated Flycatcher Cyornis rubeculoides complex in India, which consists of several forms with similar plumages and song. We used mitochondrial and nuclear DNA, plumage traits, and detailed song analysis to ascertain the taxonomic status of the different forms. The molecular data identified three primary clades: (1) in the west Himalayan foothills, (2) at higher elevations in the northeast hill states of Meghalaya, Nagaland and Mizoram, and (3) at lower elevations in the northeastern hills of Meghalaya and the east Himalayas of Arunachal Pradesh. The western clade represents nominate C. rubeculoides rubeculoides. The high-elevation eastern clade was considered to be C. rubeculoides rogersi, because it included a sample from this subspecies from near the type locality in southwest Myanmar. These two sister clades had an estimated divergence time of 1.5 million years (my). The low-elevation east clade has previously been assigned to C. rubeculoides, but we showed it is closely related to the Hainan Blue Flycatcher Cyornis hainanus, formerly thought to breed only further east, with an estimated divergence time of only ~0.8 my. This clade may represent a subspecies of C. hainanus or, given reports of widespread sympatry with C. hainanus in Thailand, a distinct species, Cyornis dialilaemus. However, more research is advocated, including molecular data, from the area of overlap. Songs were remarkably similar across all taxa. In playback experiments, C. r. rubeculoides in the west responded to all taxa. This is in agreement with recent work demonstrating that song differences and responses to songs are not always a good indicator of the progress of reproductive isolation. 相似文献
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996.
Saad M. Ahsan Raman Bakthisaran Ramakrishna Tangirala Ch. Mohan Rao 《Biochimica et Biophysica Acta (BBA)/General Subjects》2021,1865(5):129846
BackgroundαA-crystallin plays an important role in eye lens development. Its N-terminal domain is implicated in several important biological functions. Mutations in certain conserved arginine residues in the N-terminal region of αA-crystallin lead to cataract with characteristic cytoplasmic/nuclear aggregation of the mutant protein. In this study, we attempt to gain mechanistic insights into the congenital cataract caused by the R54C mutation in human αA-crystallin.MethodsWe used several spectroscopic techniques to investigate the structure and function of the wild-type and R54CαA-crystallin. Immunoprecipitation, chromatin-enrichment followed by western blotting, immunofluorescence and cell-viability assay were performed to study the interaction partners, chromatin-association, stress-like response and cell-death caused by the mutant.ResultsAlthough R54CαA-crystallin exhibited slight changes in quaternary structure, its chaperone-like activity was comparable to that of wild-type. When expressed in lens epithelial cells, R54CαA-crystallin exhibited a speckled appearance in the nucleus rather than cytoplasmic localization. R54CαA-crystallin triggered a stress-like response, resulting in nuclear translocation of αB-crystallin, disassembly of cytoskeletal elements and activation of caspase 3, leading to apoptosis. Analysis of the “interactome” revealed an increase in interaction of the mutant protein with nucleosomal histones, and its association with chromatin.ConclusionsThe study shows that alteration of “interactome” and nucleosomal association, rather than loss of chaperone-like activity, is the molecular basis of cataract caused by the R54C mutation in αA-crystallin.General significanceThe study provides a novel mechanism of cataract caused by a mutant of αA-crystallin, and sheds light on the possible mechanism of stress and cell death caused by such nuclear inclusions. 相似文献
997.
Megha Mohan Sau Lee Changning Guo S. Prasad Peri William H. Doub 《AAPS PharmSciTech》2017,18(5):1585-1594
The full-resolution next generation impactor (NGI) and three abbreviated impactor systems were used to obtain the apparent aerodynamic particle size distribution (APSD) and other quality measures for marketed dry powder inhalers (DPIs) using the compendial method and efficient data analysis (EDA). APSD for the active pharmaceutical ingredient (API) in Spiriva® Handihaler®, Foradil® Aerolizer®, and Relenza® Diskhaler® was obtained using a full-resolution NGI at 39, 60, and 90 L/min, respectively. Two reduced NGI (rNGI) configurations, the filter-only configuration (rNGI-f) and the modified-cup configuration (rNGI-mc), and the fast-screening impactor (FSI) with appropriate inserts to provide a 5-μm cut size were evaluated. The fine particle dose (FPD) obtained using the FSI for Spiriva was statistically similar to that obtained using the full NGI. However, the FPD for both Foradil and Relenza obtained using the FSI was significantly different from that obtained using the full NGI. Despite this, no significant differences were observed for the fine particle fraction (FPF) obtained using the FSI relative to that obtained from the full NGI for any of the DPIs. The use of abbreviated impactor systems appears promising with good agreement observed with the full-resolution NGI, except for small differences observed for the rNGI-mc configuration. These small differences may be product- and/or flow rate-specific, and further evaluation will be required to resolve these differences. 相似文献
998.
Imadul Islam Shendong Yuan Robert G. Wei Wei Xu Michael Morrissey Raju Mohan Dewan Zheng Andrea DiMella Laura Dunning Michael Snider Babu Subramanyam Jih-Lie Tseng Judi A. Bryant Brad O. Buckman 《Bioorganic & medicinal chemistry letters》2018,28(9):1459-1463
A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KB?=?94?nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class. 相似文献
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1000.
Firdous A. Bhat Jayshree Advani Aafaque Ahmad Khan Sonali Mohan Arnab Pal Harsha Gowda Prantar Chakrabarti T. S. Keshava Prasad Aditi Chatterjee 《Journal of cell communication and signaling》2018,12(4):737-743
Thrombopoietin (THPO), also known as megakaryocyte growth and development factor (MGDF), is a cytokine involved in the production of platelets. THPO is a glycoprotein produced by liver and kidney. It regulates the production of platelets by stimulating the differentiation and maturation of megakaryocyte progenitors. It acts as a ligand for MPL receptor, a member of the hematopoietic cytokine receptor superfamily and is essential for megakaryocyte maturation. THPO binding induces homodimerization of the receptor which results in activation of JAKSTAT and MAPK signaling cascades that subsequently control cellular proliferation, differentiation and other signaling events. Despite the importance of THPO signaling in various diseases and biological processes, a detailed signaling network of THPO is not available in any publicly available database. Therefore, in this study, we present a resource of signaling events induced by THPO that was manually curated from published literature on THPO. Our manual curation of thrombopoietin pathway resulted in identification of 48 molecular associations, 66 catalytic reactions, 100 gene regulation events, 19 protein translocation events and 43 activation/inhibition reactions that occur upon activation of thrombopoietin receptor by THPO. THPO signaling pathway is made available on NetPath, a freely available human signaling pathway resource developed previously by our group. We believe this resource will provide a platform for scientific community to accelerate further research in this area on potential therapeutic interventions. 相似文献