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31.
Dückert H Pries V Khedkar V Menninger S Bruss H Bird AW Maliga Z Brockmeyer A Janning P Hyman A Grimme S Schürmann M Preut H Hübel K Ziegler S Kumar K Waldmann H 《Nature chemical biology》2012,8(2):179-184
In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1. 相似文献
32.
Suji G Khedkar SA Singh SK Kishore N Coutinho EC Bhor VM Sivakami S 《The protein journal》2008,27(4):205-214
The binding of lipoic acid (LA), to methylglyoxal (MG) modified BSA was studied using isothermal titration calorimetry in combination with enzyme kinetics and molecular modelling. The binding of LA to BSA was sequential with two sites, one with higher binding constant and another comparatively lower. In contrast the modified protein showed three sequential binding sites with a reduction in affinity at the high affinity binding site by a factor of 10. CD results show appreciable changes in conformation of the modified protein as a result of binding to LA. The inhibition of esterase like activity of BSA by LA revealed that it binds to site II in domain III of BSA. The pH dependence of esterase activity of native BSA indicated a catalytic group with a pK(a) = 7.9 +/- 0.1, assigned to Tyr411 with the conjugate base stabilised by interaction with Arg410. Upon modification by MG, this pK(a) increased to 8.13. A complex obtained by docking of LA to BSA and BSA in which Arg410 is modified to hydroimidazolone showed that the long hydrocarbon chain of lipoic acid sits in a cavity different from the one observed for unmodified BSA. The molecular electrostatic potential showed that the modification of Arg410 reduced the positive electrostatic potential around the protein-binding site. Thus it can be concluded that the modification of BSA by MG resulted in altered ligand binding characteristics due to changes in the internal geometry and electrostatic potential at the binding site. 相似文献
33.
Kshitiz?GuptaEmail author Dina?Thomas SV?Vidya KV?VenkateshEmail author S?Ramakumar 《BMC bioinformatics》2005,6(1):105
Background
The chemical property and biological function of a protein is a direct consequence of its primary structure. Several algorithms have been developed which determine alignment and similarity of primary protein sequences. However, character based similarity cannot provide insight into the structural aspects of a protein. We present a method based on spectral similarity to compare subsequences of amino acids that behave similarly but are not aligned well by considering amino acids as mere characters. This approach finds a similarity score between sequences based on any given attribute, like hydrophobicity of amino acids, on the basis of spectral information after partial conversion to the frequency domain. 相似文献34.
A.A. Skelton V.M. Khedkar J.R. Fried 《Journal of biomolecular structure & dynamics》2016,34(3):529-539
All-atom molecular dynamics is used to investigate the transport of Na+ across a 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayer facilitated by a diazacrown hydraphile. Specifically, the free energy of Na+ passing through the bilayer is calculated using the adaptive biasing force method to study the free energy associated with the increase in Na+ transport in the presence of the hydraphile molecule. The results show that water interaction greatly influences Na+ transport through the lipid bilayer as water is pulled through the bilayer with Na+ forming a water channel. The hydraphile causes a reduction in the free energy barrier for the transport of Na+ through the head group part of the lipid bilayer since it complexes the Na+ reducing the necessity for water to be complexed and, therefore, dragged through with Na+, an energetically unfavorable process. The free energy associated with Na+ being desolvated within the bilayer is significantly decreased in the presence of the hydraphile molecule; the hydraphile increases the number of solvation states of Na+ that can be adopted, and this increase in the number of available configurations provides an entropic explanation for the success of the hydraphile. 相似文献
35.
Nathalie Lejal Sandrine Truchet Edna Bechor Edwige Bouguyon Vijay Khedkar Nicolas Bertho Jasmina Vidic Pierre Adenot Stéphanie Solier Edgar Pick Anny Slama-Schwok 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(6):1263-1275
Background
Targeting cells of the host immune system is a promising approach to fight against Influenza A virus (IAV) infection. Macrophage cells use the NADPH oxidase-2 (NOX2) enzymatic complex as a first line of defense against pathogens by generating superoxide ions O2– and releasing H2O2. Herein, we investigated whether targeting membrane -embedded NOX2 decreased IAV entry via raft domains and reduced inflammation in infected macrophages.Methods
Confocal microscopy and western blots monitored levels of the viral nucleoprotein NP and p67phox, NOX2 activator subunit, Elisa assays quantified TNF-α levels in LPS or IAV-activated mouse or porcine alveolar macrophages pretreated with a fluorescent NOX inhibitor, called nanoshutter NS1.Results
IAV infection in macrophages promoted p67phox translocation to the membrane, rafts clustering and activation of the NOX2 complex at early times. Disrupting rafts reduced intracellular viral NP. NS1 markedly reduced raft clustering and viral entry by binding to the C-terminal of NOX2 also characterized in vitro. NS1 decrease of TNF-α release depended on the cell type.Conclusion
NOX2 participated in IAV entry and raft-mediated endocytosis. NOX2 inhibition by NS1 reduced viral entry. NS1 competition with p67phox for NOX2 binding shown by in silico models and cell-free assays was in agreement with NS1 inhibiting p67phox translocation to membrane-embedded NOX2 in mouse and porcine macrophages.General significance
We introduce NS1 as a compound targeting NOX2, a critical enzyme controlling viral levels and inflammation in macrophages and discuss the therapeutic relevance of targeting the C-terminal of NADPH oxidases by probes like NS1 in viral infections. 相似文献36.
Estimating synonymous and nonsynonymous substitution rates 总被引:8,自引:4,他引:4
Partitioning the total substitution rate into synnonymous and nonsynonymous
components is a key aspect of many analyses in molecular evolution.
Numerous methods exist for estimating these rates. However, until recently
none of the estimation procedures were based on a sound statistical
footing. In this paper, the evolutionary model of Muse and Gaut (1994) is
used as the basis for two sets of parameters quantifying silent and
replacement substitution rates. The parameters are shown to be equal when
the four nucleotides are equally frequent and unequal otherwise.
Maximum-likelihood estimation of these parameters is described, and the
performance of these estimates is compared to that of existing estimation
procedures. It is shown that the estimates of Nei and Gojobori (1986) are
not unbiased for either set of parameters, although they provide very good
estimates for one set as long as sequence divergence is not too high.
However, some disturbing properties are found for the Nei and Gojobori
estimates. In particular, it is shown that the expected value of the Nei
and Gojobori estimate of silent substitution rate is a function of both the
silent and replacement substitution rates. The maximum-likelihood estimates
have no such problems.
相似文献
37.
Sudhir G. Tattikota Thomas Rathjen Jean Hausser Aditya Khedkar Uma D. Kabra Varun Pandey Matthias Sury Hans-Hermann Wessels Inês G. Mollet Lena Eliasson Matthias Selbach Robert P. Zinzen Mihaela Zavolan Sebastian Kadener Matthias H. Tsch?p Martin Jastroch Marc R. Friedl?nder Matthew N. Poy 《The Journal of biological chemistry》2015,290(33):20284-20294
In response to fasting or hyperglycemia, the pancreatic β-cell alters its output of secreted insulin; however, the pathways governing this adaptive response are not entirely established. Although the precise role of microRNAs (miRNAs) is also unclear, a recurring theme emphasizes their function in cellular stress responses. We recently showed that miR-184, an abundant miRNA in the β-cell, regulates compensatory proliferation and secretion during insulin resistance. Consistent with previous studies showing miR-184 suppresses insulin release, expression of this miRNA was increased in islets after fasting, demonstrating an active role in the β-cell as glucose levels lower and the insulin demand ceases. Additionally, miR-184 was negatively regulated upon the administration of a sucrose-rich diet in Drosophila, demonstrating strong conservation of this pathway through evolution. Furthermore, miR-184 and its target Argonaute2 remained inversely correlated as concentrations of extracellular glucose increased, underlining a functional relationship between this miRNA and its targets. Lastly, restoration of Argonaute2 in the presence of miR-184 rescued suppression of miR-375-targeted genes, suggesting these genes act in a coordinated manner during changes in the metabolic context. Together, these results highlight the adaptive role of miR-184 according to glucose metabolism and suggest the regulatory role of this miRNA in energy homeostasis is highly conserved. 相似文献
38.
Dnyaneshwar D. Subhedar Mubarak H. Shaikh Laxman Nawale Dhiman Sarkar Vijay M. Khedkar Bapurao B. Shingate 《Bioorganic & medicinal chemistry letters》2017,27(4):922-928
A series of quinoline incorporated monocarbonyl curcumin analogues was efficiently synthesized using [HDBU][HSO4] as catalyst via Knoevenagel type condensation and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG in dormant state. The analogues 3e, 3h, 4a and 4e exhibited very good antitubercular activity. The antiproliferative activity of the analogues against MCF-7, A549 and HCT-116 cell lines was evaluated using modified MTT assay and these compounds were found to be non-cytotoxic. Molecular docking study has been carried out against M. tuberculosis pantothenate synthetase (MTB PS) enzyme in an effort to enhance the understanding of their action as antitubercular agents. The potency, low cytotoxicity and selectivity of these analogues support them as valid leads for further optimization. 相似文献
39.
Microbial degradation of dibenzothiophene (DBT) beyond 3-hydroxy-2-formylbenzothiophene (HFBT), a commonly detected metabolite of the Kodama pathway for DBT metabolism, and the catabolic intermediates leading to its mineralization are not fully understood. The enrichment cultures cultivated from crude oil contaminated soil led to isolation of ERI-11; a natural mixed culture, selected for its ability to deplete DBT in basal salt medium (BSM). A bacterial strain isolated from ERI-11, and tentatively named A11, degraded more than 90 % of the initial DBT (270 µM), present as the sole carbon and sulfur source, in 72 h. Gas chromatography–mass spectrophotometry (GC–MS) analyses of the DBT degrading A11 culture medium extracts led to detection of HFBT. The metabolite HFBT, produced using A11, was used in degradation assays to evaluate its metabolism by the bacteria isolated in this study. Ultra violet–visible spectrophotometry and high-performance liquid chromatography analyses established the ability of the strain A11 to deplete HFBT, present as the sole sulfur and carbon source in BSM. GC–MS analyses showed the presence of 2-mercaptobenzoic acid in the HFBT degrading A11 culture extracts. The findings in this study establish that the environmental isolate A11 possesses the metabolic capacity to degrade DBT beyond the metabolite HFBT. The compound 2-mercaptobenzoic acid is an intermediate formed on HFBT degradation by A11. 相似文献
40.
Amol A. Nagargoje Satish V. Akolkar Madiha M. Siddiqui Dnyaneshwar D. Subhedar Jaiprakash N. Sangshetti Vijay M. Khedkar Bapurao B. Shingate 《化学与生物多样性》2020,17(2)
In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2‐chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α‐demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT. 相似文献