Current Issue : July - September Volume : 2018 Issue Number : 3 Articles : 5 Articles
Background. The development of new therapeutic strategies to treat patients for leishmaniasis has become a priority. The\nantileishmanial activity of the strychnobiflavone flavonoid was recently demonstrated against Leishmania amazonensis and\nLeishmania infantum amastigotes and promastigotes. The biological effect of this molecule was identified due to its capacity\nto interfere in the parasite mitochondrial membrane; however, the underlying molecular mechanism remains unclear. Methods\nand Results. In this study, a computational approach using bioinformatics was performed to screen biological targets of\nstrychnobiflavone in L. infantum. Computational programs, such as the target fishing approach and molecular docking assays,\nwere used. Results showed that the putative pathway targeted by strychnobiflavone in L. infantum is themethylglyoxal degradation\nsuperpathway, and one hydrolase-like protein was predicted to be the molecular target of this flavonoid in the parasites. Conclusion.\nIn this context, this study provides the basis for understanding the mechanism of action of strychnobiflavone in L. infantum and\npresents a strategy based on bioinformatics programs to screen targets of other molecules with biological action against distinct\npathogens....
Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis\n(Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis\neffects. As herbââ?¬â??drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism\nlimits clinical application of herbs and drugs in combination, this study sought to explore the enzyme\nkinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and\nin vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone\nreversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing\ninhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 Ã?¼M, respectively. Also, sauchinone\ntime-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study\nshowed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6,\n2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with\nsauchinone to mice, the systemic exposure of each drug was increased compared to that without\nsauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when\nsauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinoneââ?¬â??drug\ninteractions occurred because sauchinone inhibited the CYP-mediated metabolic activities....
Ã?²-Carbolines (Ã?²Cs) belong to the naturally occurring alkaloid family, derived from 9H-pyrido[3,4-b]indole, also known as\nnorharmane (Hnor). Knowing the importance of the Ã?²Cs alkaloid family in biological processes, a comprehensive binding study is\nreported of four Ag(I) compounds containing the ligand Hnor and having different counteranions, namely, NO3\nâË?â??, ClO4\nâË?â??, BF4\nâË?â??,\nand PF6\nâË?â??, with human serum albumin (HSA) as a model protein. Different approaches like UV-visible, fluorescence spectroscopy,\ncircular dichroism (CD), and molecular docking studies have been used for this purpose.Thefluorescence results establish that the\nphenomenon of binding of Ag(Hnor) complexes to HSA can be deduced from the static quenching mechanism. The results\nshowed a significant binding propensity of the used Ag(I) compounds towards HSA. The role of the counteranion on the binding\nof Ag(I) compounds to HSA appeared to be remarkable. Compounds with (ClO4\nâË?â??) and (NO3\nâË?â??) were found to have the most\nefficient binding towards HSA as compared to BF4\nâË?â??and PF6\nâË?â??. Circular dichroism (CD) studies made clear that conformational\nchanges in the secondary structure of HSA were induced by the presence of Ag(I) compounds. Also, the Ã?±-helical structure of HSA\nwas found to get transformed into a Ã?²-sheeted structure. Interestingly, (ClO4\nâË?â??) and (NO3\nâË?â??) compounds were found to induce\nmost substantial changes in the secondary structure of HSA. The outcome of this study may contribute to understanding the\npropensity of proteins involved in neurological diseases (such as Alzheimerââ?¬â?¢s and Parkinsonââ?¬â?¢s diseases) to undergo a similar\ntransition in the presence of Ag-Ã?²-carboline compounds....
In this study, the anticancer activity of a series of 32 molecules based on anthra[1,9-cd]pyrazol-6(2H)-one was studied by threedimensional\nquantitative structure-activity relationship (QSAR) analyses: multiple linear regression (MLR), partial least squares\n(PLS), multiple nonlinear regression (MNLR), cross-validation analyses, and Y-randomization. A theoretical study of series was\nfirstly studied using density functional theory (DFT) calculations at B3LYP/6-31 level of theory for employing to determine\nthe structural parameters and electronic properties. Then the topological descriptors were computed using ACD/ChemSketch\nand ChemDraw 8.0 programs. The RNLM, given the descriptors obtained from the MLR and PLS, exhibited a correlation\ncoefficient close to 0.91. The predictionmodels collected were confirmed by two methods of cross-validation and scrambling (or Yrandomization).\nThe strong correlation between experimental and predicted activity values was observed, indicating the validation\nand good quality of the derived QSAR model....
Dihydropyrimidinase, a dimetalloenzyme containing a carboxylated lysine within the active site, is a member of the cyclic\namidohydrolase family, which also includes allantoinase, dihydroorotase, hydantoinase, and imidase. Unlike all known dihydropyrimidinases,\nwhich are tetrameric, pseudomonal dihydropyrimidinase forms a dimer at neutral pH. In this paper, we report\nthe crystal structure of P. aeruginosa dihydropyrimidinase at pH 5.9 (PDB entry 5YKD). The crystals of P. aeruginosa dihydropyrimidinase\nbelonged to space group C2221 with cell dimensions of a 108.9, b 155.7, and c 235.6 Ã?Å¡ A. The structure of\nP. aeruginosa dihydropyrimidinase was solved at 2.17Ã?Å¡A resolution. An asymmetric unit of the crystal contained four crystallographically\nindependent P. aeruginosa dihydropyrimidinase monomers. Gel filtration chromatographic analysis of purified\nP. aeruginosa dihydropyrimidinase revealed a mixture of dimers and tetramers at pH 5.9. Thus, P. aeruginosa dihydropyrimidinase\ncan form a stable tetramer both in the crystalline state and in the solution. Based on sequence analysis and structural\ncomparison of the dimer-dimer interface between P. aeruginosa dihydropyrimidinase and Thermus sp. dihydropyrimidinase,\ndifferent oligomerization mechanisms are proposed...
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