Ernstgibson6090

The covalent protein-ligand linkage enabled structural characterization of these trapped, off-pathway oligomers using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of "post-translational chemical modification" as a tool to study biological molecular mechanisms.The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V10O286-; V10), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb10O286-; Nb10) was carried out. Four binding sites were identified, named α, β, γ, and δ, the site α being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site α is preferred by V10, whereas Nb10 is more stable at the site β; this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V10 than Nb10. Moreover, the binding mode of oxidovanadium(IV) ion, VIVO2+, formed upon the reduction of decavanadate(V) by the -SH groups of accessible cysteine residues, is also found in the catalytic site α with (His161, Asp154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V10 and its reduction product VIVO2+ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized since decavanadate prefers the nucleotide site α, Ca2+-ATP displaces V10 from this site, while the competition is less important for Nb10 because this POM shows a higher affinity for β than for site α. selleck products A relevant consequence of this paper is that other metallodrug-protein systems, in the absence or presence of eventual inhibitors and/or competition with molecules of the organism, could be studied with the same approach, suggesting important elements for an explanation of the biological data and a rational drug design.Acrolein (ACR) is found exogenously as a widespread environmental pollutant and endogenously, where it is thought to be involved as a pathogenic factor in the progression of many pathological conditions. Eliminating ACR by dietary-active substances has been found to be one potential strategy to prevent ACR-associated chronic diseases. This study first compared the scavenging ACR efficacy of four purine alkaloids, theophylline (TP), paraxanthine (PXT), theobromine (TB), and caffeine (CAF), and then, TP, CAF, and their metabolites were investigated for their ability to trap ACR in vivo. Our results indicated that TP, which possesses an -NH moiety at the N-7 position, exhibits the best ACR-trapping capacity in vitro, while CAF has a slight ability to trap ACR due to the substitutions by -CH3 at the N-1, N-3, and N-7 positions. After oral administration of TP or CAF, the ACR adducts of TP and the metabolites of TP or CAF (e.g., mono- and di-ACR-TP, mono-ACR-1,3-DMU, and mono-ACR-1-MU) were detected in urinary samples obtained from both TP- and CAF-treated mouse groups by using ultra-performance liquid chromatography-tandem mass spectrometry. The quantification studies demonstrated that TP and its metabolites significantly trapped ACR in a dose-dependent manner in vivo. Furthermore, we also detected those ACR adducts of TP and TP/CAF's metabolites in human urine after four cups of green tea (2 g tea leaf/cup) or two cups of coffee (4 g coffee/cup) were consumed per day. Those results indicated that dietary TP or CAF has the potential capacity to scavenge ACR in vivo.While bioisosteric replacements have been extensively investigated, comprehensive analyses of R-/functional groups have thus far been rare in medicinal chemistry. We introduce a new analysis concept for the exploration of chemical substituent space that is based upon bioactive analogue series as a source. From ∼24,000 analogue series, more than 19,000 substituents were isolated that were differently distributed. A subset of ∼400 substituent fragments occurred most frequently in different structural contexts. These substituents contained well-known R-groups as well as novel structures. Substitution site-specific replacement and network analysis revealed that chemically similar substituents preferentially occurred at given sites and identified intuitive substitution pathways that can be explored for compound design. Taken together, the results of our analysis provide new insights into substituent space and identify preferred substituents on the basis of analogue series. As a part of our study, all the data reported are made freely available.Sulfide accumulation in oil reservoir fluids (souring) from the activity of sulfate-reducing microorganisms (SRM) is of grave concern because of the associated health and facility failure risks. Here, we present an assessment of tungstate as a selective and potent inhibitor of SRM. Dose-response inhibitor experiments were conducted with a number of SRM isolates and enrichments at 30-80 °C and an increase in the effectiveness of tungstate treatment at higher temperatures was observed. To explore mixed inhibitor treatment modes, we tested synergy or antagonism between several inhibitors with tungstate, and found synergism between WO42- and NO2-, while additive effects were observed with ClO4- and NO3-. We also evaluated SRM inhibition by tungstate in advective upflow oil-sand-packed columns. Although 2 mM tungstate was initially sufficient to inhibit sulfidogenesis, subsequent temporal CaWO4 precipitation resulted in loss of the bioavailable inhibitor from solution and a concurrent increase in effluent sulfide. Mixing 4 mM sodium carbonate with the 2 mM tungstate was enough to promote tungstate solubility to reach inhibitory concentrations, without precipitation, and completely inhibit SRM activity. Overall, we demonstrate the effectiveness of tungstate as a potent SRM inhibitor, particularly at higher temperatures, and propose a novel carbonate-tungstate formulation for application to soured oil reservoirs.