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421.
Background
Base dependent binding of the cytotoxic alkaloid harmalol to four synthetic polynucleotides, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT), poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) was examined by various photophysical and calorimetric studies, and molecular docking.Methodology/Principal Findings
Binding data obtained from absorbance according to neighbor exclusion model indicated that the binding constant decreased in the order poly(dG-dC).poly(dG-dC)>poly(dA-dT).poly(dA-dT)>poly(dA).poly(dT)>poly(dG).poly(dC). The same trend was shown by the competition dialysis, change in fluorescence steady state intensity, stabilization against thermal denaturation, increase in the specific viscosity and perturbations in circular dichroism spectra. Among the polynucleotides, poly(dA).poly(dT) and poly(dG).poly(dC) showed positive cooperativity where as poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT) showed non cooperative binding. Isothermal calorimetric data on the other hand showed enthalpy driven exothermic binding with a hydrophobic contribution to the binding Gibbs energy with poly(dG-dC).poly(dG-dC), and poly(dA-dT).poly(dA-dT) where as harmalol with poly(dA).poly(dT) showed entropy driven endothermic binding and with poly(dG).poly(dC) it was reported to be entropy driven exothermic binding. The study also tested the in vitro chemotherapeutic potential of harmalol in HeLa, MDA-MB-231, A549, and HepG2 cell line by MTT assay.Conclusions/Significance
Studies unequivocally established that harmalol binds strongly with hetero GC polymer by mechanism of intercalation where the alkaloid resists complete overlap to the DNA base pairs inside the intercalation cavity and showed maximum cytotoxicity on HepG2 with IC50 value of 14 µM. The results contribute to the understanding of binding, specificity, energetic, cytotoxicity and docking of harmalol-DNA complexation that will guide synthetic efforts of medicinal chemists for developing better therapeutic agents. 相似文献422.
Compound prioritization from inverse docking experiment using receptor‐centric and ligand‐centric methods: a case study on Plasmodium falciparum Fab enzymes 下载免费PDF全文
Sivakumar Prasanth Kumar Himanshu A. Pandya Vishal H. Desai Yogesh T. Jasrai 《Journal of molecular recognition : JMR》2014,27(4):215-229
Prioritization of compounds using inverse docking approach is limited owing to potential drawbacks in its scoring functions. Classically, molecules ranked by best or lowest binding energies and clustering methods have been considered as probable hits. Mining probable hits from an inverse docking approach is very complicated given the closely related protein targets and the chemically similar ligand data set. To overcome this problem, we present here a computational approach using receptor‐centric and ligand‐centric methods to infer the reliability of the inverse docking approach and to recognize probable hits. This knowledge‐driven approach takes advantage of experimentally identified inhibitors against a particular protein target of interest to delineate shape and molecular field properties and use a multilayer perceptron model to predict the biological activity of the test molecules. The approach was validated using flavone derivatives possessing inhibitory activities against principal antimalarial molecular targets of fatty acid biosynthetic pathway, FabG, FabI and FabZ, respectively. We propose that probable hits can be retrieved by comparing the rank list of docking, quantitative‐structure activity relationship and multilayer perceptron models. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
423.
424.
Gabriela Petrof Arti Nanda Jake Howden Takuya Takeichi James?R. McMillan Sophia Aristodemou Linda Ozoemena Lu Liu Andrew?P. South Celine Pourreyron Dimitra Dafou Laura?E. Proudfoot Hejab Al-Ajmi Masashi Akiyama W.H.?Irwin McLean Michael?A. Simpson Maddy Parsons John?A. McGrath 《American journal of human genetics》2014,95(3):308-314
425.
426.
Lohray BB Lohray VB Srivastava BK Gupta S Solanki M Pandya P Kapadnis P 《Bioorganic & medicinal chemistry letters》2006,16(6):1557-1561
A few substituted piperazinylphenyloxazolidinone compounds 6-13 having substitution on the distant nitrogen atom of piperazine ring scaffold have been synthesized and evaluated for their antibacterial activity in Gram-positive bacteria. A few compounds showed superior in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes than linezolid and eperezolid. 相似文献
427.
Tetrahydrobiopterin is an essential cofactor for aromatic amino acid hydroxylases, ether lipid oxidase and nitric oxide synthases. Its biosynthesis in mammals is regulated by the activity of the homodecameric enzyme GCH (GTP cyclohydrolase I; EC 3.5.4.16). In previous work, catalytically inactive human GCH splice variants differing from the wild-type enzyme within the last 20 C-terminal amino acids were identified. In the present study, we searched for a possible role of these splice variants. Gel filtration profiles of purified recombinant proteins showed that variant GCHs form high-molecular-mass oligomers similar to the wild-type enzyme. Co-expression of splice variants together with wild-type GCH in mammalian cells revealed that GCH levels were reduced in the presence of splice variants. Commensurate with these findings, the GCH activity obtained for wild-type enzyme was reduced 2.5-fold through co-expression with GCH splice variants. Western blots of native gels suggest that splice variants form decamers despite C-terminal truncation. Therefore one possible explanation for the effect of GCH splice variants could be that inactive variants are incorporated into GCH heterodecamers, decreasing the enzyme stability and activity. 相似文献
428.
Horan M Newsway V Yasmin Lewis MD Easter TE Rees DA Mahto A Millar DS Procter AM Scanlon MF Wilkinson IB Hall IP Wheatley A Blakey J Bath PM Cockcroft JR Krawczak M Cooper DN 《Human genetics》2006,119(5):527-540
An increased prevalence of both hypertension and cerebrovascular stroke is apparent in growth hormone (GH) deficiency whilst hypertension is a frequent complication in acromegaly. This has suggested a possible link between GH, stature and arterial function. Since the risk of both hypertension and stroke also appears to be inversely correlated with adult height, we have instigated an exploratory study to assess whether inter-individual variation in the genes encoding human growth hormone (GH1) and the GH receptor (GHR) might be associated with an increased risk of hypertension and stroke. GH1 promoter haplotypes were found to differ significantly not only between hypertensive patients (n=111) and controls (n=121) but also between stroke patients (n=155) and controls (n=158). Intriguingly, the association between GH1 promoter haplotype and risk of hypertension was much greater in females than in males. An inverse correlation between height and central systolic blood pressure was apparent in both hypertensive patients and normal controls but was much stronger in individuals carrying at least one GH1 promoter risk haplotype. The GH1 genotype therefore constitutes a risk factor for hypertension that interacts with stature. A strong association was found between the presence of at least one GH1 risk haplotype and a family history of stroke at an early age (odds ratio: 9.07, 95% confidence interval: 1.14–72.22). Three novel GH variants (Arg16His, Phe176Cys, Cys189Arg) were identified during the course of this study. Although two exhibited markedly reduced biological activity in vitro, their clinical significance remains unclear. No association was found between GHR genotype and either hypertension or stroke, nor was any interaction noted between GHR and GH1 genotypes in terms of a disease association. However, an association between GHRd3 genotype and hypertension was observed among stroke patients, particularly females. Elevated HDL was found to be a risk factor for hypertension in individuals lacking a copy of the GHRd3 allele. Weak associations with GHR genotype were also noted for peripheral systolic and diastolic blood pressure in hypertensive patients. Although the underlying mechanisms are still unclear, our findings are consistent with a complex relationship between height, hypertension, GH1 promoter haplotype, GHR polymorphism and the risk of stroke. 相似文献
429.
Brijesh Kumar Srivastava Rina Soni Jayendra Z. Patel Amit Joharapurkar Nisha Sadhwani Samadhan Kshirsagar Bhupendra Mishra Vijay Takale Sunil Gupta Purvi Pandya Prashant Kapadnis Manish Solanki Harilal Patel Prasenjit Mitra Mukul R. Jain Pankaj R. Patel 《Bioorganic & medicinal chemistry letters》2009,19(9):2546-2550
A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models. 相似文献
430.
Sudheer Pamidiamarri DV Pandya N Reddy MP Radhakrishnan T 《Molecular biology reports》2009,36(5):901-907
Genus Jatropha with 172 species having significant economic importance belongs to the family Euphorbiaceae. There are no reports on molecular
characterization and phylogenetic relationship among the species of Jatropha. Hence, the present study was undertaken to assess the extent of genetic variability that exist and also to establish phylogenetic
relationship among Jatropha curcas, J. glandulifera, J. gossypifolia, J. integerrima, J. multifida, J. podagrica and J. tanjorensis using RAPD and AFLP. The percentage of loci that are polymorphic among the species studied was found to be 97.74% by RAPD
and 97.25% by AFLP. The mean percentage of polymorphism (PP) was found to be 68.48 by RAPD and 71.33 by AFLP. The phylogram
generated with RAPD and AFLP data showed maximum similarity. With the generated data maximum relatedness was found between
J. curcas and J. integerrima this may be the reason for the success of inter hybrid crosses between these two species. Neither RAPD nor AFLP data generated
in this study supports the view of J. tanjorensis, a natural interspecific hybrid between J. curcas and J. gossypifolia. The present study concludes that both RAPD and AFLP techniques are comparable in divergence studies of Jatropha species. The markers generated by RAPD and AFLP can be employed efficiently for interspecific hybrids identification, marker
assisted selection and genetic resource management. 相似文献