The blockage of the hERG K+ channels is closely associated with lethal cardiac arrhythmia. The notorious ligand promiscuity of this channel earmarked hERG as one of the most important antitargets to ...be considered in early stages of drug development process. Herein we report on the development of an innovative and freely accessible web server for early identification of putative hERG blockers and non‐blockers in chemical libraries. We have collected the largest publicly available curated hERG dataset of 5,984 compounds. We succeed in developing robust and externally predictive binary (CCR≈0.8) and multiclass models (accuracy≈0.7). These models are available as a web‐service freely available for public at http://labmol.farmacia.ufg.br/predherg/. Three following outcomes are available for the users: prediction by binary model, prediction by multi‐class model, and the probability maps of atomic contribution. The Pred‐hERG will be continuously updated and upgraded as new information became available.
In this paper, chitosan was reacted with monochloroacetic acid under alkaline conditions to prepare carboxymethyl chitosan. A 23 full-factorial central composite design was applied to evaluate the ...effect of molar ratio sodium hydroxide (NaOH)/Chitosan (Ch), time and molar ratio monochloroacetic acid (MCA)/Chitosan (Ch) on the reaction yield and on the characteristics of carboxymethyl chitosan such as average degree of substitution (DS¯) and solubility. An optimization strategy based on response surface methodology was used together with the desirability function approach to optimize this process. The occurrence of carboxymethylation was evidenced by FTIR and 1H NMR spectroscopy. The optimum conditions for carboxymethylation process were found to be 12.4, 10.6h and 5 for molar ratio sodium hydroxide (NaOH)/Chitosan (Ch), time and molar ratio monochloroacetic acid (MCA)/Chitosan (Ch), respectively. Under these optimal conditions, it was possible to obtain carboxymethyl chitosan with DS¯ of 1.86 and solubility of 99.6%. X-ray diffraction and thermogravimetry analysis showed that crystallinity and thermal stability of derivatives was lower than chitosan and decreased with increase of DS¯.
•A bioactive fucomannogalactan (FMG-Hm) was isolated from H. marmoreus mushroom.•It consists of α-Galp (1→6) main chain, branched at O-2 by α-Fucp and β-Manp units.•FMG-Hm reduced malignancy ...parameters in melanoma cells, without toxicity.•This heteropolysaccharide exhibited promising in vitro antimelanoma effects.
A fucomannogalactan (FMG-Hm), with a molecular weight of 17.1 kDa, obtained from fruiting bodies of Hypsizygus marmoreus exhibited promising in vitro antimelanoma effects. FMG-Hm was not cytotoxic, nor did it alter the cell morphology and proliferation, but was able to inhibit colony-forming ability and cell migration in B16-F10 murine melanoma cells. An analysis of the monosaccharide composition indicated that FMG-Hm was composed of fucose, mannose, and galactose in a ratio of 1.00:1.08:3.17. The FMG-Hm was structurally characterized based on methylation analysis, partial acid hydrolysis, and NMR experiments. The results indicated that FMG-Hm contained a α-(1→6)-linked galactopyranosyl main chain, partially substituted at O-2 by non-reducing ends of α-L-fucopyranose and β-D-mannopyranose. The predicted structure of the heteropolysaccharide was established as:
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Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle ...derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials.
In the present work, we developed an experimental class for undergraduate students concerning the linear synthesis of 2-phenylimidazo1,2-αpyridine through mechanochemical techniques. This approach ...aims to conceptualize the green chemistry principles through a safe, robust, atom-economic, energy-efficient, and solvent-free method for preparing these classes of compounds by manual grinding and vortex mixing. The methodology was easily applied in experimental classes for chemistry students and could be easily expanded to other courses such as pharmacy and biotechnology.
Infections caused by Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa foremost among them, constitute a major worldwide health problem. Bioinformatics methodologies are being used ...to rationally design new antimicrobial peptides, a potential alternative for treating these infections. One of the algorithms used to develop antimicrobial peptides is the Joker, which was used to design the peptide PaDBS1R6. This study evaluates the antibacterial activities of PaDBS1R6 in vitro and in vivo, characterizes the peptide interaction to target membranes, and investigates the PaDBS1R6 structure in contact with mimetic vesicles. Moreover, we demonstrate that PaDBS1R6 exhibits selective antimicrobial activity against Gram-negative bacteria. In the presence of negatively charged and zwitterionic lipids the structural arrangement of PaDBS1R6 transits from random coil to α-helix, as characterized by circular dichroism. The tertiary structure of PaDBS1R6 was determined by NMR in zwitterionic dodecylphosphocholine (DPC) micelles. In conclusion, PaDBS1R6 is a candidate for the treatment of nosocomial infections caused by Gram-negative bacteria, as template for producing other antimicrobial agents.
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•PaDBS1R6 presented in-helix conformation when in contact with anionic lipid membranes•Antibacterial selectivity of PaDBS1R6 against Gram-negative bacteria•PaDBS1R6 was active in vivo in murine intraperitoneal and skin infection models.
Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul ...(EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-β-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-β-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-β-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-β-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-β-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.
Herein, we describe a urea hydrogen peroxide-mediated sustainable protocol for the synthesis of selenylated imidazo2,1-bthiazole by using half molar equivalent diorganyl diselenides in ethyl ...lactate as a greener solvent. The reaction features high yields, easy performance on gram scale, metal-free conditions, as well as applicability to imidazopyridine and imidazopyrimidine.
In the early 2000s, the first articles regarding the calculation of NMR parameters for natural products appeared in the literature. Since then, modelling 1H and 13C chemical shifts and spin–spin ...coupling constants for this class of compounds has experienced a remarkable increase in precision, accessibility, and application, leading to considerable advances in the field. More recently, significant contributions from several authors have led to continuous growth in this research field, updating and broadening the simulation of NMR parameters, in particular with the application of new techniques for data treatment. Nowadays, such studies are routinely found in the high impact literature. In this review, we intend to cover the general guidelines and the main advances in NMR calculations of natural products published since 2012. We intend to address the bottlenecks of quantum chemical calculations of NMR parameters, including mathematical definitions, updates, and a discussion of relevant examples, and to highlight novel tools, for example DU8+, CP3, DP4, DP4+ and J-DP4. We will cover all aspects of NMR simulation focusing on natural products, from the fundamentals to the new computational toolboxes available, combining advanced quantum chemical calculations with complex upstream data processing and machine learning.
Mastoparans are cationic peptides with multifunctional pharmacological properties. Mastoparan‐R1 and mastoparan‐R4 were computationally designed based on native mastoparan‐L from wasps and have ...improved therapeutic potential for the control of bacterial infections. Here, we evaluated whether these peptides maintain their activity against Escherichia coli strains under a range of salt concentrations. We found that mastoparan‐R1 and mastoparan‐R4 preserved their activity under the conditions tested, including having antibacterial activities at physiological salt concentrations. The overall structure of the peptides was investigated using circular dichroism spectroscopy in a range of solvents. No significant changes in secondary structure were observed (random coil in aqueous solutions and α‐helix in hydrophobic and anionic environments). The three‐dimensional structures of mastoparan‐R1 and mastoparan‐R4 were elucidated through nuclear magnetic resonance spectroscopy, revealing amphipathic α‐helical segments for Leu3‐Ile13 (mastoparan‐R1) and Leu3‐Ile14 (mastoparan‐R4). Possible membrane‐association mechanisms for mastoparan‐R1 and mastoparan‐R4 were investigated through surface plasmon resonance and leakage studies with synthetic POPC and POPC/POPG (4:1) lipid bilayers. Mastoparan‐L had the highest affinity for both membrane systems, whereas the two analogs had weaker association, but improved selectivity for lysing anionic membranes. This finding was also supported by molecular dynamics simulations, in which mastoparan‐R1 and mastoparan‐R4 were found to have greater interactions with bacteria‐like membranes compared with model mammalian membranes. Despite having a few differences in their functional and structural profiles, the mastoparan‐R1 analog stood out with the highest activity, greater bacteriostatic potential, and selectivity for lysing anionic membranes. This study reinforces the potential of mastoparan‐R1 as a drug candidate.
Mastoparans are cationic peptides with multifunctional pharmacological properties. Two molecules, mastoparan‐R1 and mastoparan‐R4, derived from wasp toxin, exhibit antimicrobial activity against bacteria. These nontoxic peptides hold promise as potential new drugs. Here, we have performed structural and functional characterization of these molecules and we report exciting findings for addressing infections caused by antibiotic‐resistant bacteria and developing a model for novel, targeted antibacterial compounds.
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