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1.
Int J Mol Sci ; 23(2)2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35054939

RESUMO

BACKGROUND: Naringenin (NAR) is a flavonoid with excellent antioxidant and neuroprotective potential that is limited by its low solubility. Thus, solid dispersions with ß-cyclodextrin (ß-CD), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), hydroxypropylmethylcellulose (HPMC), and microenvironmental pH modifiers were prepared. METHODS: The systems formation analysis was performed by X-Ray Powder Diffraction (XRPD) and Fourier-transform infrared spectroscopy (FT-IR). Water solubility and dissolution rates were studied with a pH of 1.2 and 6.8. In vitro permeability through the gastrointestinal tract (GIT) and the blood-brain barrier (BBB) was assessed with the parallel artificial membrane permeability assay (PAMPA) assay. The antioxidant activity was studied with the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and cupric ion reducing antioxidant capacity (CUPRAC) assays, while in vitro enzymes studies involved the inhibition of acetylcholinesterase, butyrylcholinesterase, and tyrosinase. For the most promising system, in silico studies were conducted. RESULTS: NAR solubility was increased 458-fold by the solid dispersion NAR:HP-ß-CD:NaHCO3 in a mass ratio of 1:3:1. The dissolution rate was elevated from 8.216% to 88.712% in a pH of 1.2 and from 11.644% to 88.843% in a pH of 6.8 (within 3 h). NAR GIT permeability, described as the apparent permeability coefficient, was increased from 2.789 × 10-6 cm s-1 to 2.909 × 10-5 cm s-1 in an acidic pH and from 1.197 × 10-6 cm s-1 to 2.145 × 10-5 cm s-1 in a basic pH. NAR BBB permeability was established as 4.275 × 10-6 cm s-1. The antioxidant activity and enzyme inhibition were also increased. Computational studies confirmed NAR:HP-ß-CD inclusion complex formation. CONCLUSIONS: A significant improvement in NAR solubility was associated with an increase in its biological activity.

2.
J Phys Chem B ; 125(39): 10900-10916, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34550710

RESUMO

The structure and conformation of glycosaminoglycans (GAGs) are of central importance to understand the mechanisms behind their functions in biological systems. Due to the inherent chemical and structural heterogeneity of GAGs, focusing on longer, naturally existing GAG chains hinders drawing conclusions on the influence of the chemical functionalization on the basic conformational degree of freedom, that is, the dynamic shape of glycosidic linkage present in the particular disaccharide repeating unit. In the present study, we have considered the complete set of 106 GAG-related disaccharides, being potential building blocks for longer GAG chains (including hyaluronan, chondroitin, keratan, dermatan, and heparan). Both the unfunctionalized units and all possible combinations of either partially or fully sulfated derivatives contribute to this number. The unbiased and enhanced sampling molecular dynamics simulations provide a link to understand the influence of sulfation on the conformational properties of GAG glycosidic linkages. Residue-residue hydrogen bonding is not significant for either the glycosidic linkage conformation or its flexibility. It was found that in the majority of cases, the dominating conformation of the linkage is weakly affected by sulfation and the main role is played by the steric and stereoelectronic effects. However, there exist numerous cases where sulfation increases the contribution of alternative conformations to a nonnegligible extent and, in some rare cases (restricted to disaccharides building heparan), leads to the reorientation of the glycosidic linkage. The identified sulfation sites, being the most important in this context, are C6 and C3 at the GlcNAc residue. Finally, the full set of free energy maps relying on the glycosidic dihedral angle values for diverse GAG disaccharides are provided; they may be used for further studies, focused on longer GAG chains.


Assuntos
Dissacarídeos , Glicosaminoglicanos , Ácido Hialurônico , Conformação Molecular , Simulação de Dinâmica Molecular
3.
Org Biomol Chem ; 19(33): 7190-7201, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34382051

RESUMO

d-Allosamine is a rare sugar in Nature but its pyranoid form has been found α-linked in the core region of the lipopolysaccharide from the Gram-negative bacterium Porphyromonas gingivalis and in the chitanase inhibitor allosamidin, then ß-linked and N-acetylated. In water solution the monosaccharide N-acetyl-d-allosamine (d-AllNAc) shows a significant presence of four tautomers arising from pyranoid and furanoid ring forms and anomeric configurations. The furanoid ring forms both showed 3JH1,H2≈ 4.85 Hz and to differentiate the anomeric configurations a series of chemical shift anisotropy/dipole-dipole cross-correlated relaxation NMR experiments was performed in which the α-anomeric form showed notable different relaxation rates for its components of the H1 doublet, thereby making it possible to elucidate the anomeric configuration of each of the furanoses. The conformational preferences of the different forms of d-AllNAc were investigated by 3JHH, 2JCH and 3JCH coupling constants from NMR experiments, molecular dynamics simulations and density functional theory calculations. The pyranose form resides in the 4C1 conformation and the furanose ring form has the majority of its conformers located on the South-East region of the pseudorotation wheel, with a small population in the Northern hemisphere. The tautomeric equilibrium was quite sensitive to changes in temperature, where the ß-anomer of the pyranoid ring form decreased upon a temperature increase while the other forms increased.

4.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445315

RESUMO

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing's syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11ß-HSD1. Inhibition of 11ß-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing's syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11ß-HSD isoforms. For most of them, over 50% inhibition of 11ß-HSD1 and less than 45% inhibition of 11ß-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11ß-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Tiazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/química , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Hidrocortisona/química , Hidrocortisona/metabolismo , Ligação Proteica , Tiazóis/farmacologia
5.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063471

RESUMO

The formation of cefuroxime axetil+cyclodextrin (CA+CD) complexes increases the aqueous solubility of CA, improves its physico-chemical properties, and facilitates a biomembrane-mediated drug delivery process. In CD-based tablet formulations, it is crucial to investigate the molecular details of complexes in final pharmaceutical preparation. In this study, Raman spectroscopy and mapping were applied for the detection and identification of chemical groups involved in α-, ß-, γ-, and 2-hydroxypropyl-ß-CD (2-HP- ß-CD)+CA complexation process. The experimental studies have been complemented by molecular dynamics-based investigations, providing additional molecular details of CA+CD interactions. It has been demonstrated that CA forms the guest-host type inclusion complexes with all studied CDs; however, the nature of the interactions is slightly different. It seems that both α- and ß-CD interact with furanyl and methoxy moieties of CA, γ-CD forms a more diverse pattern of interactions with CA, which are not observed in other CDs, whereas 2HP-ß-CD binds CA with the contribution of hydrogen bonding. Apart from supporting this interpretation of the experimental data, molecular dynamics simulations allowed for ordering the CA+CD binding affinities. The obtained results proved that the molecular details of the host-guest complexation can be successfully predicted from the combination of Raman spectroscopy and molecular modeling.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina , Cefuroxima/análogos & derivados , Ciclodextrinas/química , Análise Espectral Raman , 2-Hidroxipropil-beta-Ciclodextrina/química , Cefuroxima/química , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Vibração
6.
Materials (Basel) ; 14(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918857

RESUMO

In the present work, extraction with a solvent (cold acetone) was used to extract the assimilation pigments from spinach leaves. Then, the sorption capacity of selected plastics granules (polyvinyl chloride-PVC, polypropylene-PP, polyethylene-PE of different densities) was tested for the selective isolation of chlorophylls. Quantification of chlorophylls by HPLC (Zorbax Eclipse XDB-C18 column, the mobile phase: Acetonitrile/methanol/ethyl acetate 6:2:2, v/v) was based on chlorophyll-a content as the most common chlorophyll. The performed experiments prove that PVC containing electronegative chlorine exhibits favorable interactions toward chlorophyll by creating stable molecular complexes. The Fourier Transform Raman Spectroscopy (FT-Raman) and the molecular modeling were used to elucidate the structure of the created complexes. The optimal extraction requirements, the mass of sorbent, water-acetone ratio, time, and the composition of the elution solvent were all established. The optimized extraction conditions ensured a maximum extraction yield of chlorophylls of 98%. The chlorophyll-rich sorbent was re-extracted by acetone, leading to the recovery of 91% of chlorophylls in one step, adding the possibility of its re-use. The proposed effective and ecological method of obtaining the green dye from plants is cheap, simple, and efficient, avoiding organic solvents, utilizing the most widely used synthetic polymers in the world, being products difficult for utilization. The possibility to remove chosen fungicides cyprodinil, chlorothalonil, and thiabendazone from plant extract by PVC was also examined. The described method proposes a new application of synthetic polymers, which meets the criteria of sustainable green chemistry, simultaneously reaching the growing demand for pure natural compounds in the pharmaceutical and food industries.

7.
Int J Mol Sci ; 22(8)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919582

RESUMO

Piperine is an alkaloid that has extensive pharmacological activity and impacts other active substances bioavailability due to inhibition of CYP450 enzymes, stimulation of amino acid transporters and P-glycoprotein inhibition. Low solubility and the associated low bioavailability of piperine limit its potential. The combination of piperine with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) causes a significant increase in its solubility and, consequently, an increase in permeability through gastrointestinal tract membranes and the blood-brain barrier. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) were used to characterize interactions between piperine and HP-ß-CD. The observed physicochemical changes should be combined with the process of piperine and CD system formation. Importantly, with an increase in solubility and permeability of piperine as a result of interaction with CD, it was proven to maintain its biological activity concerning the antioxidant potential (2,2-diphenyl-1-picryl-hydrazyl-hydrate assay), inhibition of enzymes essential for the inflammatory process and for neurodegenerative changes (hyaluronidase, acetylcholinesterase, butyrylcholinesterase).


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Alcaloides/química , Benzodioxóis/química , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Animais , Barreira Hematoencefálica/metabolismo , Varredura Diferencial de Calorimetria , Humanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
Bioorg Chem ; 110: 104819, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33752144

RESUMO

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC50 values in the range of 5.56-16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC50 values in the range of 6.69-10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC50 values about 32 µM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC50. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ftalimidas/farmacologia , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Ftalimidas/química , Relação Estrutura-Atividade , Tiazóis/química , Células Tumorais Cultivadas
9.
J Chem Theory Comput ; 17(4): 2575-2585, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33703894

RESUMO

In this paper, we present the results of molecular dynamics simulations aimed at critical comparison of classical, biomolecular force fields (FFs) in the context of their capabilities to describe the structural and thermodynamic features of carbohydrate-protein interactions. We have considered the three main families of FFs (CHARMM, GROMOS, and GLYCAM/AMBER) by applying them to investigate the seven different carbohydrate-protein complexes. The results indicate that although the qualitative pattern of several structural descriptors (intermolecular hydrogen bonding, ligand dynamic location, etc.) is conserved among the compared FFs, there also exists a number of significant divergences (mainly the patterns of contacts between particular amino acid residues and bound carbohydrate). The carbohydrate-protein unbinding free energies also vary from one FF to another, displaying diversified trends in deviations from the experimental data. The magnitude of those deviations is not negligible and indicates the need for refinement in the currently existing combinations of carbohydrate- and protein-dedicated biomolecular force fields. In spite of the lack of explicit functional terms responsible for the corresponding intermolecular forces, all tested FFs are capable of adequately reproducing the CH-π interactions, crucial for carbohydrate-protein binding.


Assuntos
Carboidratos/química , Simulação de Dinâmica Molecular , Proteínas/química , Sítios de Ligação , Termodinâmica
10.
Carbohydr Polym ; 256: 117566, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483067

RESUMO

This study presents a novel model of homogalacturonan (HG) based on the dissipative particle dynamics (DPD). The model was applied to investigate the mechanism of self-aggregation of low-methoxylated homogalacturonan in aqueous solutions in the absence of cations. The coarse-grained model provided new insights into the structural features of HG aggregates and networks in aqueous solutions. Depending on the properties and concentration of polysaccharides, two major patterns of self-assembly were observed for HG - ellipsoidal aggregates and a continuous three-dimensional network. Simulations showed that a decrease in the degree of dissociation of HG results in a higher rate of self-aggregation, as well as facilitating the formation of larger assemblies or thicker nanofilaments depending on the type of final self-assembly. Simulations of polysaccharides of different chain lengths suggested the existence of a structural threshold for the formation of a spatial network for HG consisting of less than 35 GalA units.


Assuntos
Ácidos Hexurônicos/química , Pectinas/química , Polissacarídeos/química , Calibragem , Ácidos Carboxílicos/química , Cátions , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Estrutura Molecular , Tamanho da Partícula , Água/química
11.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374358

RESUMO

Progressive increase in bacterial resistance has caused an urgent need to introduce new antibiotics, one of them being oxazolidinones with their representative tedizolid. Despite the broad spectrum of activity of the parent tedizolid, it is characterized by low water solubility, which limits its use. The combination of the active molecule with a multifunctional excipient, which is cyclodextrins, allows preservation of its pharmacological activity and modification of its physicochemical properties. Therefore, the aim of the study was to change the dissolution rate and permeability through the model membrane of tedizolid by formation of solid dispersions with a cyclodextrin. The research included identification of tedizolid-hydroxypropyl-ß-cyclodextrin (tedizolid/HP-ß-CD) inclusion complex by thermal method (Differential Scanning Colorimetry), spectroscopic methods (powder X-ray diffraction, Fourier-Transform Infrared spectroscopy), and molecular docking. The second part of the research concerned the physicochemical properties (dissolution and permeability) and the biological properties of the system in terms of its microbiological activity. An increase in the dissolution rate was observed in the presence of cyclodextrin, while maintaining a high permeation coefficient and high microbiological activity. The proposed approach is an opportunity to develop drug delivery systems used in the treatment of resistant bacterial infections, in which, in addition to modifying the physicochemical properties caused by cyclodextrin, we observe a favorable change in the pharmacological potential of the bioactives.


Assuntos
Antibacterianos/farmacologia , Ciclodextrinas/administração & dosagem , Sistemas de Liberação de Medicamentos , Oxazolidinonas/administração & dosagem , Tetrazóis/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Farmacorresistência Bacteriana , Concentração de Íons de Hidrogênio , Simulação de Acoplamento Molecular , Estresse Oxidativo , Permeabilidade , Pós , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , beta-Ciclodextrinas/química
12.
Int J Mol Sci ; 21(23)2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33260768

RESUMO

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a-3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Teoria da Densidade Funcional , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Tropanos/síntese química , Tropanos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioinformática , Humanos , Concentração Inibidora 50 , Camundongos , Eletricidade Estática , Termodinâmica
13.
Materials (Basel) ; 13(22)2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33233399

RESUMO

Zeolites are materials with known sorption properties. The sorption is thought to progress mainly by ion exchange with Na+, K+, Mg2+, Ca2+ or H+ from the zeolite exchange sites. The aim of the study was to compare the sorption properties of natural and synthetic zeolites on the example of the removal of selected metals from aqueous acidic solutions. Uptake experiments for selected ions of chromium, manganese, selenium, nickel, cobalt, and iron were performed using the batch and kinetic column methods. The sorption of the individual metal ions in mg per 1g of sorbent was determined for each sorbent. The relative affinity sequence of the examined cations toward the various sorbent was presented. The Langmuir model was used to model the adsorption equilibrium. Vermiculite under 1 mm of diameter (SF), Na-X, and Na-A were proved to be the most suitable for the individual uptake of studied metal ions. It was observed that the behavior of selenium ions differed from the remaining ones which was interpreted that selenium undergoes adsorption in the anionic form. The fixed-bed column studies were performed using Na-A, ensuring the sorption of selenium in the presence of iron(III) ions. The experiments were conducted using Na-X zeolite pre-loaded by Fe(III) as well as unmodified sorbent eluted by an equimolar mixture containing 100 ppm of Fe and Se. Obtained results prove that selenium sorption improves if other metal ions such as iron appear in the acidic solution. That efficient selenium sorption conditions can be applied to remove selenium which was recognized as toxic at higher levels.

14.
J Chem Inf Model ; 60(11): 5424-5436, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32937074

RESUMO

Chirality plays an essential role in chemical and biological sciences. At the molecular level, the effects associated with this phenomenon can be studied by using the well-established technique of molecular dynamics simulations. In this work, we present several approaches suited for the molecular dynamics-based free energy calculation in chiral systems. In particular, we have proposed and tested the following strategies relying on the application of general, enhanced sampling methods: (i) biased sampling in the two-dimensional space, along the coordinates defined by the values of the selected torsional angles; (ii) biased sampling in the one- or two-dimensional space, along the path-based coordinate(s); (iii) rational alteration of the system's Hamiltonian in order to enable the interconversion between stereoisomers and reweighting the biased distribution of configurations; (iv) using the free energy landscape generated within approaches (i) or (ii) as time-independent bias in order to further improve sampling efficiency and simultaneously account for multiple chiral centers. All approaches have been tested on a set of model compounds (fenoterol, fructofuranose, and bromochlorofluoromethane), demonstrating the good performance but also some differences in the range of their applicabilities.


Assuntos
Simulação de Dinâmica Molecular , Entropia
15.
Carbohydr Polym ; 240: 116266, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32475556

RESUMO

Inulin, levan and arabinan are the polysaccharides that consist of exclusively furanose units. To date, their conformational features studied at the molecular scale have remained largely unexplained. To tackle this issue, we have performed a series of explicit-solvent molecular dynamics simulations, carried out within the furanose-dedicated force field. None of the polysaccharides exhibits a single, dominating structure type. Instead, they create a large number of separated conformational states originating from the intensive rotation around the φ and ω glycosidic angles. 21-helices are the preferential conformational forms for all compounds but they appear only locally, at the length of several consecutive residues. The flexibility of all three furanose-based polysaccharides is much greater in relation to the (1-4)-linked pyranose polysaccharides and is comparable to that of (1-6)-linked pyranoses. The dynamic geometries of both furanose rings and glycosidic linkages are nearly unchanged independently if considering them at the level of mono-, di- or polysaccharides.


Assuntos
Frutanos/química , Inulina/química , Polissacarídeos/química , Configuração de Carboidratos , Simulação de Dinâmica Molecular
16.
Materials (Basel) ; 13(11)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532041

RESUMO

The cell membrane is a complex system that consists of lipids, proteins, polysaccharides, and amphiphilic phospholipids. It plays an important role in ADME processes that are responsible for the final pharmaceutical effects of xenobiotics (bioavailability, activity). To study drug-membrane interaction at the molecular level, several high-performance liquid chromatography (HPLC) membrane model systems have been proposed which are mimicking mainly its lipid character. The aim of this work was to study interactions of new synthesized antiepileptic compounds of 4-alkyl-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives with Chirobiotic column containing glycoprotein ligand attached to the silica matrix. The affinity of the analytes to immobilized glycoprotein ligand was examined chromatographically in reversed-phase mode. The thermodynamics of interactions between bioactive compounds and teicoplanin was studied in terms of the van't Hoff linear relationship ln k vs. 1/T in the range of 5-45 °C. Change in enthalpy (ΔH°), change in entropy (ΔS°) and change in Gibbs free energy (ΔG°) were estimated utilizing graphical extrapolation and interpolation methods. The density functional theory (DFT) approach and docking simulations were used to get the molecular interpretation and prove the obtained experimental results. Cross-correlations of chromatographic and thermodynamic parameters with non-empirical topological and quantum chemical indices suggest that the polarizability of analytes appears to be responsible for the interactions of the tested molecules with teicoplanin and, ultimately, their retention on the column. Experimental and theoretical parameters were subjected to statistical analysis using regression models. Partial least squares (PLS) regression model showed the usefulness of the experimentally measured parameter φ0 (MeOH) to discriminate between anticonvulsant active and inactive 1,2,4-triazole-3-thione derivatives. Obtained results point out the usefulness of interaction of potential anticonvulsants with glycoprotein class of compounds to anticipate their activity.

17.
Phys Chem Chem Phys ; 22(25): 14364-14374, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568319

RESUMO

Regarding their application in the field of molecular sciences, machine learning (ML) methods are capable of combining the high accuracy of ab initio potentials with an efficiency closer to that of classical molecular mechanics. By relying on the reference data (e.g., atomic configurations and corresponding energies), the ML algorithms can reconstruct the potential energy surface for simple molecular systems, which may subsequently serve as a computationally inexpensive force field. The accuracy of such an ML force field is highly dependent on the character of the dataset that was used for its training. In this work, we show that omitting the high-energy states, which results from following the Boltzmann distribution, may lead to a catastrophic loss of accuracy in certain regions of the configurational phase space. To overcome this challenge, we have proposed an alternative solution for generating the ML input data. The most essential step is the biased subsampling of the configurations, aimed at increasing the population of hardly accessible states, usually located on energy barriers. The applicability of the proposed procedure is demonstrated on the example of conformational rearrangements in the two flexible, heterocyclic molecules. This approach provides an essential component required to obtain the ML force fields, accurate within the whole configurational phase space of the system.

18.
J Biomol Struct Dyn ; 38(11): 3359-3370, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31429635

RESUMO

Furanoses are an important group of natural saccharides as well as the components of crucial biomolecules such as nucleic acids. Contrary to pyranoses, they exhibit much larger inherent flexibility which amplifies the difficulty in determining their conformational preferences. We carried out a series of molecular dynamics simulations oriented at systematic analysis of conformational properties of unfunctionalized furanose monosaccharides (all members of d-aldopento- and d-aldotetrofuranoses). The results concern the description of the influence of the ring substituents (with respect of their type, location and orientation) on the geometry of the furanose ring. The main energetic contributions to the barriers on the pseudorotation path are associated with the following types of interactions: (i) unfavorable interactions between uniformly oriented vicinal ring substituents; (ii) unfavorable syn-axial interactions between uniformly oriented non-vicinal ring substituents; (iii) endo-anomeric effect. The interactions resulting from the presence of the particular ring substituents are not additive and cannot be used to obtain the pseudorotational profiles. The orientation of the hydroxymethyl group and the conformation of the ring are not mutually correlated. Contrary, the ring conformational preferences are correlated with the orientation of the lactol group via the influence of the exo-anomeric effect. Finally, analogously to pyranoses, also in the case of furanoses, the intramolecular hydrogen bonding does not play any essential role in conformational properties of monosaccharides.Communicated by Ramaswamy H. Sarma.


Assuntos
Simulação de Dinâmica Molecular , Ácidos Nucleicos , Ligação de Hidrogênio , Conformação Molecular
19.
Eur J Med Chem ; 184: 111765, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629163

RESUMO

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC50 (8.74 µM) value which is significantly lower than the activity of trimethoprim (IC50 39.23 µM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC50 51.88-83.49 µM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC30 ∼ 880 µM). The most active compound 3k showed tyrosinase inhibition effect, with IC50 value of 328.5 µM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC50 15.9 and 15.5 µM), respectively, which is ten times higher than well-known antioxidant BHT.


Assuntos
Antioxidantes/farmacologia , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antiprotozoários/síntese química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiofenos/química , Toxoplasma/enzimologia , Toxoplasma/crescimento & desenvolvimento , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
20.
J Sep Sci ; 42(16): 2628-2639, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168923

RESUMO

Liquid chromatography coupled to spectrophotometric detection of new antiepileptic compounds, 1,2,4-triazole-3-thione derivatives, on immobilized artificial membrane phosphatidylcholine is reported. The curves representing the relationship between ln k versus 1/T generated under isocratic conditions by the use of methanol and acetonitrile-containing eluent systems have been constructed in order to determine the thermodynamic parameters: the enthalpies, entropies and the relative free energies. The hydrocarbon chains of analytes significantly influenced the membrane behavior of the whole molecules. Excellent correlations of the theoretical lipophilicity with the experimental thermodynamic descriptors, have confirmed contribution of the hydrophobic interactions in the retention process. However, presence of sulfur or oxygen as heteroatoms at R1 substituents in the 1,2,4-triazole ring appears to be responsible for more pronounced selectivity of these compounds on the phosphatidylcholine stationary phase. Molecular dynamics simulations revealed the selective preferences of the phosphatidylcholine with respect to the compounds with either ether of sulfide moieties. Experimental and theoretical set-ups resulted in corresponding outcomes.


Assuntos
Materiais Biomiméticos/química , Varredura Diferencial de Calorimetria , Fosfatidilcolinas/química , Termodinâmica , Tionas/análise , Triazóis/análise , Cromatografia Líquida , Estrutura Molecular , Espectrofotometria
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