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Shivalika Pathania Vinay Randhawa 《Journal of biomolecular structure & dynamics》2020,38(17):5108-5125
AbstractNipah Virus (NiV) is a newly emergent paramyxovirus that has caused various outbreaks in Asian countries. Despite its acute pathogenicity and lack of approved therapeutics for human use, there is an urgent need to determine inhibitors against NiV. Hence, this work includes prospection of potential entry inhibitors by implementing an integrative structure- and network-based drug discovery approach. FDA-approved drugs were screened against attachment glycoprotein (NiV-G, PDB: 2VSM), one of the prime targets to inhibit viral entry, using a molecular docking approach that was benchmarked both on CCDC/ASTEX and known NIV-G inhibitor set. The predicted small molecules were prioritized on the basis of topological analysis of the chemical-protein interaction network, which was inferred by integrating the drug-target network, NiV-human interaction network, and human protein-protein interaction network. A total of 17 drugs were predicted to be NiV-G inhibitors using molecular docking studies that were further prioritized to 3 novel leads???Nilotinib, Deslanoside and Acetyldigitoxin???on the basis of topological analysis of inferred chemical-protein interaction network. While Deslanoside and Acetyldigitoxin belong to an already known class of anti-NiV inhibitors, Nilotinib belongs to Benzenoids chemical class that has not been reported hitherto for developing anti-NiV inhibitors. These identified drugs are expected to be successful in further experimental evaluation and therefore could be used for anti-Nipah drug discovery. Apart, we also obtained various insights into the underlying chemical-protein interaction network, based on which several important network nodes were predicted. The applicability of our proposed approach was also demonstrated by prospecting for anti-NiV phytochemicals on an independent dataset.Communicated by Ramaswamy H. Sarma 相似文献
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Angiogenesis has a key role in the tumor progression and metastasis; targeting endothelial cell proliferation has emerged as a promising therapeutic strategy for the prevention of cancer. Previous studies have revealed a complex association between the process of angiogenesis and autophagy and its outcome on tumorigenesis. Autophagy, also known as type-II cell death, has been identified as an alternative way of cell killing in apoptotic-resistant cancer cells. However, its involvement in chemoresistance and tumor promotion is also well known. In this study, we used a derivate of natural product magnolol (Ery5), a potent autophagy inducer, to study the association between the autophagy and angiogenesis in both in vitro and in vivo model system. We found that the robust autophagy triggered by Ery5, inhibited angiogenesis and caused cell death independent of the apoptosis in human umbilical cord vein endothelial cells and PC-3 cells. Ery5 induced autophagy effectively inhibited cell proliferation, migration, invasion and tube formation. We further demonstrated that Ery5-mediated autophagy and subsequent inhibition of angiogenesis was reversed when autophagy was inhibited through 3-methyl adenine and knocking down of key autophagy proteins ATG7 and microtubule-associated protein light chain 3. While evaluating the negative regulation of autophagy on angiogenesis, it was interesting to find that angiogenic environment produced by the treatment of VEGF and CoCl2 remarkably downregulated the autophagy and autophagic cell death induced by Ery5. These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer. 相似文献
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The phage Mu transpososome is assembled by interactions of transposase subunits with the left (L) and right (R) ends of Mu and an enhancer (E) located in between. A metastable three-site complex LER progresses into a more stable type 0 complex in which a tetrameric transposase is poised for DNA cleavage. "Difference topology" has revealed five trapped negative supercoils within type 0, three contributed by crossings of E with L and R, and two by crossings of L with R. This is the most complex DNA arrangement seen to date within a recombination synapse. Contrary to the prevailing notion, the enhancer appears not to be released immediately following type 0 assembly. Difference topology provides a simple method for determining the ordered sequestration of DNA segments within nucleoprotein assemblies. 相似文献
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Grainge I Pathania S Vologodskii A Harshey RM Jayaram M 《Journal of molecular biology》2002,320(3):515-527
Flp and Cre-mediated recombination on symmetrized FRT and loxP sites, respectively, in circular plasmid substrates yield both DNA inversion and deletion. However, upon sequestering three negative supercoils outside the recombination complex using the resII-resIII synapse formed by Tn3 resolvase and the LER synapse formed by phage Mu transposase in the case of Flp and Cre, respectively, the reactions are channeled towards inversion at the expense of deletion. The inversion product is a trefoil, its unique topology being conferred by the external resolvase or LER synapse. Thus, Flp and Cre assign their symmetrized substrates a strictly antiparallel orientation with respect to strand cleavage and exchange. These conclusions are supported by the product profiles from tethered parallel and antiparallel native FRT sites in dilution and competition assays. Furthermore, the observed recombination bias favoring deletion over inversion in a nicked circular substrate containing two symmetrized FRT sites is consistent with the predictions from Monte Carlo simulations based on antiparallel synapsis of the DNA partners. 相似文献
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Arvind Gulati Natasha Sharma Pratibha Vyas Swati Sood Praveen Rahi Vijaylata Pathania Ramdeen Prasad 《Archives of microbiology》2010,192(11):975-983
An efficient phosphate-solubilizing plant growth–promoting Acinetobacter rhizosphaerae strain BIHB 723 exhibited significantly higher solubilization of tricalcium phosphate (TCP) than Udaipur rock phosphate (URP),
Mussoorie rock phosphate (MRP) and North Carolina rock phosphate (NCRP). Qualitative and quantitative differences were discerned
in the gluconic, oxalic, 2-keto gluconic, lactic, malic and formic acids during the solubilization of various inorganic phosphates
by the strain. Gluconic acid was the main organic acid produced during phosphate solubilization. Formic acid production was
restricted to TCP solubilization and oxalic acid production to the solubilization of MRP, URP and NCRP. A significant increase
in plant height, shoot fresh weight, shoot dry weight, root length, root dry weight, and root, shoot and soil phosphorus (P)
contents was recorded with the inoculated treatments over the uninoculated NP0K or NPTCPK treatments. Plant growth promotion as a function of phosphate solubilization suggested that the use of bacterial strain
would be a beneficial addition to the agriculture practices in TCP-rich soils in reducing the application of phosphatic fertilizers. 相似文献
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Pathania S Nguyen J Hill SJ Scully R Adelmant GO Marto JA Feunteun J Livingston DM 《Molecular cell》2011,44(2):235-251
BRCA1 contributes to the response to UV irradiation. Utilizing its BRCT motifs, it is recruited during S/G2 to UV-damaged sites in a DNA replication-dependent but nucleotide excision repair (NER)-independent manner. More specifically, at UV-stalled replication forks, it promotes photoproduct excision, suppression of translesion synthesis, and the localization and activation of replication factor C complex (RFC) subunits. The last function, in turn, triggers post-UV checkpoint activation and postreplicative repair. These BRCA1 functions differ from those required for DSBR. 相似文献
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Anup S. Pathania Suresh Kumar Santosh K. Guru Shashi Bhushan Parduman R. Sharma Sravan K. Aithagani Parvinder P. Singh Ram A. Vishwakarma Ajay Kumar Fayaz Malik 《PloS one》2014,9(11)
Tryptanthrin is a natural product which has been reported to have several medicinal properties. In this study, we tried to investigate the detailed molecular mechanism of its bromo analogue (TBr), a potent cytotoxic agent in the induction of cancer cell death. It was found that TBr primarily targets STAT3 and ERK signaling during the induction of apoptosis in several human leukemia cell lines. In HL-60 cells, TBr treatment caused early down regulation of p-STAT3 with concomitant up regulation of p-ERK which led to the activation of intrinsic and extrinsic pathways of apoptosis. The mechanism of TBr mediated inhibition of p-STAT3 was found to be due to the activation of ubiquitin dependent degradation of tyrosine 705 and serine 727 p-STAT3. As IL-6 is the main driver of the STAT3 pathway, the effect of TBr on cell death was subdued when treated in the combination with IL-6 in HL60 cells. Interestingly, PD98059 significantly reduced the apoptotic effects of TBr, thus showing the direct involvement of p-ERK in TBr mediated cell death. It was further shown that apoptotic protein Bax silencing in HL-60 cells resists TBr mediated ERK dependent apoptosis. In summary, for the first time we report the mechanism of TBr mediated cell death in human leukemia cell lines by targeting STAT3 and ERK pathways. 相似文献
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Santosh Kumar Srivastava V. Rajesh Iyer Tamoghna Ghosh Paramesh Ramulu Lambadi Ranjana Pathania Naveen Kumar Navani 《Nucleic acids research》2016,44(5):2451-2461
Advances in chemical biology have led to selection of synthetic functional nucleic acids for in vivo applications. Discovery of synthetic nucleic acid regulatory elements has been a long-standing goal of chemical biologists. Availability of vast genome level genetic resources has motivated efforts for discovery and understanding of inducible synthetic genetic regulatory elements. Such elements can lead to custom-design of switches and sensors, oscillators, digital logic evaluators and cell–cell communicators. Here, we describe a simple, robust and universally applicable module for discovery of inducible gene regulatory elements. The distinguishing feature is the use of a toxic peptide as a reporter to suppress the background of unwanted bacterial recombinants. Using this strategy, we show that it is possible to isolate genetic elements of non-genomic origin which specifically get activated in the presence of DNA gyrase A inhibitors belonging to fluoroquinolone (FQ) group of chemicals. Further, using a system level genetic resource, we prove that the genetic regulation is exerted through histone-like nucleoid structuring (H-NS) repressor protein. Till date, there are no reports of in vivo selection of non-genomic origin inducible regulatory promoter like elements. Our strategy opens an uncharted route to discover inducible synthetic regulatory elements from biologically-inspired nucleic acid sequences. 相似文献