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991.
SAR study and conformational analysis of a series of novel peptide G protein‐coupled receptor kinase 2 inhibitors 下载免费PDF全文
Marina Sala Ermelinda Vernieri Antonio Limatola Alessia Bertamino Simona Musella Paolo Grieco Bruno Trimarco Ettore Novellino Guido Iaccarino Pietro Campiglia 《Biopolymers》2014,101(1):121-128
G protein‐coupled receptor kinase 2 (GRK2) plays a central role in the cellular transduction network. In particular, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. Thereby, its inhibition offers a potential therapeutic solution to several pathological conditions. In the present study, we performed a SAR study and a NMR conformational analysis of peptides derived from HJ loop of GRK2 and able to selectively inhibit GRK2. From Ala‐scan and d ‐Ala point replacement, we found that Arg residues don't affect the inhibitory properties, while a d ‐amino acid at position 5 is key to the activity. Conformational analysis identified two β‐turns that involve N‐terminal residues, followed by a short extended region. These information can help the design of peptides and peptido‐mimetics with enhanced GRK2 inhibition properties. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 121–128, 2014. 相似文献
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993.
Volatile Compounds of Viola odorata Absolutes: Identification of Odorant Active Markers to Distinguish Plants Originating from France and Egypt 下载免费PDF全文
Laure Saint‐Lary Céline Roy Jean‐Philippe Paris Pascal Tournayre Jean‐Louis Berdagué Olivier P. Thomas Xavier Fernandez 《化学与生物多样性》2014,11(6):843-860
Absolutes isolated from Viola odorata leaves, valuable materials for the flavor and fragrance industry, were studied. Violets are mainly cultivated in France and Egypt and extracted locally. The absolutes of the two origins showed different olfactory profiles both in top and heart notes, as evidenced by sensory analysis. The aims of this study were i) to characterize the volatile compounds, ii) to determine the odorant‐active ones, and iii) to identify some markers of the plant origin. Two complementary analytical methods were used for these purposes, i.e., headspace solid‐phase microextraction (HS‐SPME) using different fiber coatings followed by GC/MS analysis and gas chromatography – olfactometry/mass spectrometry (GC‐O/MS) applied to violet leaf extracts. From a total of 70 identified compounds, 61 have never been reported so far for this species, 17 compounds were characterized by both techniques (with seven among them known from the literature), 23 compounds were solely identified by HS‐SPME GC/MS (among them only two being already mentioned as components of violet absolutes in the literature), and, finally, 30 compounds were only identified by GC‐O/MS. According to the HS‐SPME GC/MS analyses, ethyl hexanoate and (2E,6Z)‐nona‐2,6‐dienol were specific volatile compounds of the sample with French origin, while (E,E)‐hepta‐2,4‐dienal, hexanoic acid, limonene, tridecane, and eugenol were specific of the samples with Egyptian origin. Additional compounds that were not detected by HS‐SPME GC/MS analysis were revealed by GC‐O analyses, some of them being markers of origin. Pent‐1‐en‐3‐ol, 3‐methylbut‐2‐enal, 2‐methoxy‐3‐(1‐methylethyl)pyrazine, 4‐ethylbenzaldehyde, β‐phenethyl formate, and 2‐methoxy‐3‐(2‐methylpropyl)pyrazine revealed to be odorant markers of the French sample, whereas cis‐rose oxide, trans‐rose oxide, and 3,5,5‐trimethylcyclohex‐2‐enone were odorant markers of the Egyptian samples. 相似文献
994.
Concomitant activation of the PI3K/Akt and ERK1/2 signalling is involved in cyclic compressive force‐induced IL‐6 secretion in MLO‐Y4 cells 下载免费PDF全文
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997.
Molecular dynamics simulation studies for DNA sequence recognition by reactive metabolites of anticancer compounds 下载免费PDF全文
Khaled M. Tumbi Prajwal P. Nandekar Naeem Shaikh Siddharth S. Kesharwani Abhay T. Sangamwar 《Journal of molecular recognition : JMR》2014,27(3):138-150
The discovery of novel anticancer molecules 5F‐203 (NSC703786) and 5‐aminoflavone (5‐AMF, NSC686288) has addressed the issues of toxicity and reduced efficacy by targeting over expressed Cytochrome P450 1A1 (CYP1A1) in cancer cells. CYP1A1 metabolizes these compounds into their reactive metabolites, which are proven to mediate their anticancer effect through DNA adduct formation. However, the drug metabolite–DNA binding has not been explored so far. Hence, understanding the binding characteristics and molecular recognition for drug metabolites with DNA is of practical and fundamental interest. The present study is aimed to model binding preference shown by reactive metabolites of 5F‐203 and 5‐AMF with DNA in forming DNA adducts. To perform this, three different DNA crystal structures covering sequence diversity were selected, and 12 DNA‐reactive metabolite complexes were generated. Molecular dynamics simulations for all complexes were performed using AMBER 11 software after development of protocol for DNA‐reactive metabolite system. Furthermore, the MM‐PBSA/GBSA energy calculation, per‐nucleotide energy decomposition, and Molecular Electrostatic Surface Potential analysis were performed. The results obtained from present study clearly indicate that minor groove in DNA is preferable for binding of reactive metabolites of anticancer compounds. The binding preferences shown by reactive metabolites were also governed by specific nucleotide sequence and distribution of electrostatic charges in major and minor groove of DNA structure. Overall, our study provides useful insights into the initial step of mechanism of reactive metabolite binding to the DNA and the guidelines for designing of sequence specific DNA interacting anticancer agents. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
998.
Liliya Vugmeyster Tien Do Dmitry Ostrovsky Riqianq Fu 《Protein science : a publication of the Protein Society》2014,23(2):145-156
Thermostable villin headpiece protein (HP67) consists of the N‐terminal subdomain (residues 10–41) and the autonomously folding C‐terminal subdomain (residues 42–76) which pack against each other to form a structure with a unified hydrophobic core. The X‐ray structures of the isolated C‐terminal subdomain (HP36) and its counterpart in HP67 are very similar for the hydrophobic core residues. However, fine rearrangements of the free energy landscape are expected to occur because of the interactions between the two subdomains. We detect and characterize these changes by comparing the µs‐ms time scale dynamics of the methyl‐bearing side chains in isolated HP36 and in HP67. Specifically, we probe three hydrophobic side chains at the interface of the two subdomains (L42, V50, and L75) as well as at two residues far from the interface (L61 and L69). Solid‐state deuteron NMR techniques are combined with computational modeling for the detailed characterization of motional modes in terms of their kinetic and thermodynamic parameters. The effect of interdomain interactions on side chain dynamics is seen for all residues but L75. Thus, changes in dynamics because of subdomain interactions are not confined to the site of perturbation. One of the main results is a two‐ to threefold increase in the value of the activation energies for the rotameric mode of motions in HP67 compared with HP36. Detailed analysis of configurational entropies and heat capacities complement the kinetic view of the degree of the disorder in the folded state. 相似文献
999.
Bochra Amina Bahri Mariem Saadani Ghaya Mechichi Wafa Rouissi 《Journal of Phytopathology》2019,167(6):351-362
Anthracnose Citrus disease has been associated with several symptoms worldwide and it is recently compromising Citrus production in the Mediterranean area. Four species complexes are mainly involved: Colletotrichum boninense, C. acutatum, C. gloeosporioides and C. truncatum. In this study, we investigated the genetic diversity of Colletotrichum spp. in Tunisia associated with wither‐tip of twigs on Citrus. Specific primers ITS4‐CgInt allowed the identification of C. gloeosporioides species complex in all the 54 isolates, sampled from three regions and four Citrus species. Overall, our genotypic analysis using 10 SSR markers showed a moderate diversity level in Tunisian C. gloeosporioides population and highlighted that C. gloeosporioides reproduce mainly clonally. In addition, heterothallic isolates were present in our population, suggesting that the pathogen population may undergo parasexual recombinations. The highest genetic diversity in C. gloeosporioides was recorded in Nabeul and on orange, which likely constitutes the area and the host of origin for the Citrus anthracnose disease in Tunisia. In addition, no population subdivision was detected at the geographic, host species or cultivars’ origin levels. However, our study identified two genetic subpopulations and indicated a rapid C. gloeosporioides population change at temporal scale that should be further examined over several consecutive growing seasons in order to understand its population dynamics. 相似文献
1000.
Filipe V. Almeida Stephen M. Douglass Mitchell E. Fane Ashani T. Weeraratna 《Pigment cell & melanoma research》2019,32(2):237-247
This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen‐activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition—it contains fibroblasts, immune cells, endothelial cells, adipocytes, and among others. In addition, the TME provides “non‐homeostatic” levels of oxygen, nutrients (hypoxia and metabolic stress), and extracellular matrix proteins, creating a pro‐tumorigenic niche that drives resistance to MAPKi treatment. In this review, we will focus on how changes in the tumor microenvironment regulate MAPKi resistance. 相似文献