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51.
Brett J. Schuchardt David C. Mikles Vikas Bhat Caleb B. McDonald Marius Sudol Amjad Farooq 《Journal of molecular recognition : JMR》2015,28(4):220-231
While being devoid of the ability to recognize ligands itself, the WW2 domain is believed to aid ligand binding to the WW1 domain in the context of a WW1–WW2 tandem module of WW domain‐containing oxidoreductase (WWOX) tumor suppressor. In an effort to test the generality of this hypothesis, we have undertaken here a detailed biophysical analysis of the binding of WW domains of WWOX alone and in the context of the WW1–WW2 tandem module to an array of putative proline‐proline‐x–tyrosine (PPXY) ligands. Our data show that while the WW1 domain of WWOX binds to all ligands in a physiologically relevant manner, the WW2 domain does not. Moreover, ligand binding to the WW1 domain in the context of the WW1–WW2 tandem module is two‐to‐three‐fold stronger than when treated alone. We also provide evidence that the WW domains within the WW1–WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. Of particular note is the observation that the physical association of the WW2 domain with WW1 blocks access to ligands. Consequently, ligand binding to the WW1 domain not only results in the displacement of the WW2 lid but also disrupts the physical association of WW domains in the liganded conformation. Taken together, our study underscores a key role of allosteric communication in the ability of the WW2 orphan domain to chaperone physiological action of the WW1 domain within the context of the WW1–WW2 tandem module of WWOX. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
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Vikas SharmaJente Boonen Nagendra S. ChauhanMayank Thakur Bart De SpiegeleerV.K. Dixit 《Phytomedicine》2011,18(13):1161-1169
According to Indian Systems of Medicine, Spilanthes acmella (L.) Murr. (Family - Asteraceae), is considered effective in the treatment of sexual deficiencies especially due to ageing. In the present study, characterization of ethanolic extracts of the Spilanthes acmella flower and its effect on general mating pattern, penile erection and serum hormone levels of normal male Wistar albino rats were investigated and compared with sildenafil citrate. In vitro nitric oxide release was also investigated in human corpus cavernosum cell line. As N-alkylamides are a promising group, their profiling was performed using a gradient reversed phase high performance liquid chromatography/electrospray ionization ion trap mass spectrometry (HPLC/ESI-MS) method on an embedded polar column. MS1 and MS2 fragmentation data were used for identification purposes. For assessment of sexual behavior, animals were divided into five groups of eight male rats. The extracts (50, 100 and 150 mg/kg body weight/day) and sildenafil citrate (5 mg/kg body weight/day) (positive control) were administered orally for 28 days. The behavioral and sexual parameters were observed at days 0, 15, 28 and after a lapse of 7 and 14 days of discontinuance of drug treatment. Five N-isobutylamides, one 2-methylbutylamide and one 2-phenylethylamide were identified. The orally administered extract had a dose dependent positive effect on mounting frequency, intromission frequency and ejaculation frequency and the most significant effects (p < 0.05) were observed at 150 mg/kg treatment, even after a lapse of 7 and 14 days of discontinuance of drug treatment. A dose dependent effect was also observed on the FSH, LH and testosterone serum levels. With 150 mg/kg of ethanolic extract the values for FSH, LH and testosterone were 3.10 ± 0.25 mlU/ml, 6.87 ± 0.18 mlU/ml and 3.72 ± 0.12 ng/ml, respectively. In vitro nitric oxide release was 21.7 ± 2.9 μM, which was significantly higher compared to the control group (p < 0.01). Sildenafil citrate exhibited also a significant effect on NO release, but no effect on hormone levels of rats was observed. The aphrodisiac potential of an ethanolic Spilanthes acmella extract was demonstrated in vitro and in vivo. N-Alkylamides might attribute to the improved sexual potential. Study lends support to the traditional utilization of S. acmella as a sexual stimulating agent. 相似文献
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Stasi LP Bhimani K Borriello M Canciani L Caselli G Colace F Ferioli C Kaswala M Mennuni L Piepoli T Pucci S Salvi M Shirsath V Zanelli T Zerbi S 《Bioorganic & medicinal chemistry letters》2011,21(21):6336-6340
The construction of a EP(4) antagonists pharmacophore model and the discovery of a highly potent oxepinic series of EP(4) antagonists is discussed. Compound 1a exhibits an excellent selectivity profile toward EP(2) receptor subtype and low cytochrome P450 inhibition potential. 相似文献
56.
The aim of the present study was to investigate the mechanism of androgen-mediated, prolonged sperm-storage in the female reproductive tract of the bat, Scotophilus heathii. The bat treated in vivo with flutamide, an androgen antagonist, showed loss of spermatozoa at the storage site, utero-tubal junction. Immunocytochemistry and Western blot analysis revealed the presence of increased expression of Bcl2 in the epithelial cell lining of the utero-tubal junction during the period of sperm-storage. Treatment with testosterone in vitro caused a significant dose-dependent increase in expression of the survival factor Bcl2, whereas treatment with flutamide together with testosterone caused a significant decline in Bcl2 in the utero-tubal junction of S. heathii. Together with the expression of Bcl2, the utero-tubal junction also expresses the death signal, caspase3. Expression of caspase3 decreased during January, but increased in February during the late stage of sperm storage. Androgen stimulated Bcl2 synthesis in the utero-tubal junction via the non-genomic MAP kinase signaling pathway. In conclusion, this study suggests that androgen promotes sperm storage in S. heathii by stimulating the survival factor Bcl2 in the utero-tubal junction. It is further hypothesized that a balance between the survival factor, Bcl2, and the death signal, caspase3, determines the duration of sperm storage in S. heathii. 相似文献
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Ghule Vikas Dasharath Sarangapani Radhakrishnan Jadhav Pandurang M. Tewari Surya P. 《Journal of molecular modeling》2011,17(6):1507-1515
Different nitro azole isomers based on five membered heterocyclics were designed and investigated using computational techniques
in order to find out the comprehensive relationships between structure and performances of these high nitrogen compounds.
Electronic structure of the molecules have been calculated using density functional theory (DFT) and the heat of formation
has been calculated using the isodesmic reaction approach at B3LYP/6-31G* level. All designed compounds show high positive
heat of formation due to the high nitrogen content and energetic nitro groups. The crystal densities of these energetic azoles
have been predicted with different force fields. All the energetic azoles show densities higher than 1.87 g/cm3. Detonation properties of energetic azoles are evaluated by using Kamlet-Jacobs equation based on the calculated densities
and heat of formations. It is found that energetic azoles show detonation velocity about 9.0 km/s, and detonation pressure
of 40GPa. Stability of the designed compounds has been predicted by evaluating the bond dissociation energy of the weakest
C-NO2 bond. The aromaticity using nucleus independent chemical shift (NICS) is also explored to predict the stability via delocalization
of the π-electrons. Charge on the nitro group is used to assess the impact sensitivity in the present study. Overall, the
study implies that all energetic azoles are found to be stable and expected to be the novel candidates of high energy density
materials (HEDMs). 相似文献
59.
This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting
systematic structure–property relationships. Molecular structures with diverse energetic substituents at varying positions
in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation
by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro
derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro
heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm−3, and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics
in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish
sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics.
The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas
generators and smoke-free pyrotechnic fuels as they are rich in nitrogen content. 相似文献