Mechanismus účinku většiny léčiv je založen na jejich interakci s molekulovými cíli v organismu, tj. biologickými makromolekulami, jako jsou proteiny nebo nukleové kyseliny. Mezi faktory ovlivňující sílu navázání molekuly léčiva na jeho biologický cíl patří celkový počet interakcí, jejich charakter a z něj vyplývající energie vazby. Hodnota energie vazby je zásadním parametrem pro odhad síly interakce. Základní typy těchto intermolekulárních interakcí jsou v přehledovém článku definovány, schematicky znázorněny a doplněny údaji o energii vazby. Dále jsou uvedeny další aspekty navazování léčiv na molekulové cíle, např. solvatace molekul ve vodném pro středí nebo vzdálenost interagujících chemických funkčních skupin. Znalost struktur molekulárních cílů i díky úspěchu současných modelů nám umožňuje tyto interakce využívat pro návrh nových léčiv.
The mechanism of action of most drugs is based on their interaction with molecular targets in the organism, i.e., biological macromolecules such as proteins or nucleic acids. Factors influencing the strength of binding of a drug molecule to its biological target include the total number of interactions, their character, and the resulting binding energy. The value of binding energy is an essential parameter for estimating the strength of the interaction. The basic types of these intermolecular interactions are defined, schematically illustrated, and supported with data on binding energy in this review article. Other aspects of drug binding to molecular targets are also presented, e.g., the solvation of molecules in aqueous environment or the distance of interacting chemical functional groups. Knowledge of the structures of molecular targets and the progress of current models allows us to use these interactions to design new drugs.
Glycosphingolipids (GSLs) are amphipathic lipids composed of a sphingoid base and a fatty acyl attached to a saccharide moiety. GSLs play an important role in signal transduction, directing proteins within the membrane, cell recognition, and modulation of cell adhesion. Gangliosides and sulfatides belong to a group of acidic GSLs, and numerous studies report their involvement in neurodevelopment, aging, and neurodegeneration. In this study, we used an approach based on hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry (HRMS/MS) to characterize the glycosphingolipid profile in rat brain tissue. Then, we screened characterized lipids aiming to identify changes in glycosphingolipid profiles in the normal aging process and tau pathology. Thorough screening of acidic glycosphingolipids in rat brain tissue revealed 117 ganglioside and 36 sulfatide species. Moreover, we found two ganglioside subclasses that were not previously characterized-GT1b-Ac2 and GQ1b-Ac2. The semi-targeted screening revealed significant changes in the levels of sulfatides and GM1a gangliosides during the aging process. In the transgenic SHR24 rat model for tauopathies, we found elevated levels of GM3 gangliosides which may indicate a higher rate of apoptotic processes.
- MeSH
- chromatografie kapalinová MeSH
- G(M3) gangliosid genetika MeSH
- geneticky modifikovaná zvířata MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- krysa rodu rattus MeSH
- kyselé glykosfingolipidy genetika izolace a purifikace MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus patologie MeSH
- neurofibrily genetika patologie MeSH
- proteiny tau genetika MeSH
- stárnutí genetika patologie MeSH
- sulfoglykosfingolipidy izolace a purifikace metabolismus MeSH
- tauopatie genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Candida albicans has several virulence factors at its disposal, including yeast-hyphal transition associated with biofilm formation, phospholipases, proteases and hemolytic activity, all of which contribute to its pathogenesis. We used synthetic derivative LL-III/43 of antimicrobial peptide lasioglossin LL-III to enhance effect of azoles on attenuation of C. albicans virulence factors. LL-III/43 was able to inhibit initial adhesion or biofilm formation of C. albicans strains at 50 µM. Azoles, however, were ineffective at this concentration. Using fluorescently labeled LL-III/43, we observed that peptide covered C. albicans cells, partially penetrated through their membranes and then accumulated inside cells. LL-III/43 (25 µM) in combination with clotrimazole prevented biofilm formation already at 3.1 µM clotrimazole. Neither LL-III/43 nor azoles were able to significantly inhibit phospholipases, proteases, or hemolytic activity of C. albicans. LL-III/43 (25 µM) and clotrimazole (50 µM) in combination decreased production of these virulence factors, and it completely attenuated its hemolytic activity. Scanning electron microscopy showed that LL-III/43 (50 µM) prevented C. albicans biofilm formation on Ti-6Al-4 V alloy used in orthopedic surgeries and combination of LL-III/43 (25 µM) with clotrimazole (3.1 µM) prevented biofilm formation on urinary catheters. Therefore, mixture of LL-III/43 and clotrimazole is suitable candidate for future pharmaceutical research.
- MeSH
- antifungální látky farmakologie MeSH
- azoly farmakologie MeSH
- biofilmy účinky léků růst a vývoj MeSH
- Candida albicans účinky léků MeSH
- erytrocyty účinky léků MeSH
- faktory virulence MeSH
- fosfolipasy antagonisté a inhibitory MeSH
- hemolýza účinky léků MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- kationické antimikrobiální peptidy chemická syntéza farmakokinetika MeSH
- lidé MeSH
- proteasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Poly(2-alkyl-2-oxazoline)s (PAOx) represent a class of emerging polymers that can substitute or even outperform poly(ethylene oxide) (PEO) standard in various applications. Despite the great advances in PAOx research, there is still a gap in the direct experimental comparison of antifouling properties between PAOx and the golden standard PEO when exposed to blood. Motivated by this, we developed a straightforward protocol for the one-pot PAOx polymerization and surface coating by a "grafting to-" approach. First, we synthesized a library of hydrophilic poly(2-methyl-2-oxazoline)s (PMeOx) and poly(2-ethyl-2-oxazoline)s (PEtOx) with molar mass ranging from 1.5 to 10 kg/mol (DP = 16-115). The PAOx living chains were directly terminated by amine and hydroxyl groups of polydopamine (PDA) anchor layer providing the highest so far reported grafting densities ranging from 0.2 to 2.1 chains/nm2. In parallel, PEO chains providing the same degree of polymerization (molar mass from 1.2 to 5 kg/mol, DP = 28-116) bearing thiol groups were grafted to PDA. The thickness, surface-related parameters, covalent structure, and antifouling properties of the resulting polymer brushes were determined via various surface sensitive techniques. The comparison of the synthesized PAOx and PEO brushes led us to the conclusion that at the same surface-related parameters, PMeOx brushes show significantly better antifouling character when challenged against human blood plasma.
- MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- krevní plazma účinky léků MeSH
- lidé MeSH
- molekulová hmotnost MeSH
- oxazoly chemická syntéza chemie farmakologie MeSH
- polyaminy chemická syntéza chemie farmakologie MeSH
- polyethylenglykoly chemická syntéza chemie farmakologie MeSH
- polymerizace MeSH
- polymery chemická syntéza chemie farmakologie MeSH
- povrchové vlastnosti účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
gamma-Fe2O3 nanoparticles obtained by coprecipitation of Fe(II) and Fe(III) chlorides with a base and subsequent oxidation were coated with a shell of hydrophilic biocompatible poly(N,N-dimethylacrylamide) (PDMAAm). Various initiators were attached to the iron oxide surface to enable the use of the "grafting-from" approach for immobilization of PDMAAm. They included 2,2'-azobis(2-methylpropanimidamide) dihydrochloride (AMPA), 2,2'-azobis(N-hydroxy-2-methylpropanimidamide) dihydrochloride (ABHA) and 4-cyano-4-{[1-cyano-3-(N-hydroxycarbamoyl)-1-methylpropyl]azo}pentanoic acid (CCHPA). Engulfment of PDMAAm-coated y-Fe2O3 nanoparticles by murine J774.2 macrophages was investigated. Only some nanoparticles were engulfed by the macrophages. PDMAAm-AMPA-gamma-Fe2O3 and PDMAAm-ABHA-y-Fe2O3 nanoparticles were rapidly engulfed by the cells. In contrast, neat y-Fe2O3 and PDMAAm-CCHPA-gamma-Fe2O3 particles induced formation of transparent vacuoles indicating toxicity of the particles. Thus, PDMAAm-coated AMPA- and ABHA-gamma-Fe2O3 nanoparticles can be recommended as non-toxic labels for mammalian cells.
- MeSH
- akrylamidy chemie farmakologie MeSH
- buněčné linie MeSH
- fluorescenční mikroskopie MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- magnetické jevy MeSH
- magnety * MeSH
- makrofágy cytologie účinky léků metabolismus MeSH
- myši MeSH
- nanočástice chemie ultrastruktura MeSH
- polymerizace účinky léků MeSH
- radiační rozptyl MeSH
- savci metabolismus MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- světlo MeSH
- velikost částic MeSH
- železité sloučeniny farmakologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Adhesion of bacteria to epithelial tissue is an essential step in the progression of the urinary tract infections. Reduction of virulence factors responsible for microbial attachment may help to decrease or inhibit colonization of the host organism by pathogens. In the age of increasing bacterial antibiotic resistance, more and more attention is being paid to the use of plants and/or their bioactive components in the prevention and treatment of human infections. Asiatic acid (AA) and ursolic acid (UA), two plant secondary metabolites, were used as potential antibacterial agents. The current study aimed to determine the possible impact of AA and UA on morphology, hydrophobicity, and adhesion of clinical uropathogenic Escherichia coli strains (UPEC) to the uroepithelial cells. Our work describes for the first time the effects exerted by AA and UA on virulence factors of UPECs. The impact of both acids on the cell surface hydrophobicity of the investigated strains was very weak. The results clearly show the influence of AA and UA on the presence of P fimbriae and curli fibers, morphology of the UPECs cells and their adhesion to epithelium; however, some differences between activities of AA and UA were found.
- MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální adheze účinky léků MeSH
- epitelové buňky cytologie mikrobiologie MeSH
- faktory virulence MeSH
- fylogeneze MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- pentacyklické triterpeny farmakologie MeSH
- rostlinné extrakty farmakologie MeSH
- sekvenční analýza DNA MeSH
- triterpeny farmakologie MeSH
- uropatogenní Escherichia coli účinky léků růst a vývoj MeSH
- urotel cytologie mikrobiologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: The herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. METHODS: Molecular modeling capable of evaluating interactions of AAI with the active site of human CYP1A1, 1A2 and 1B1 under the reductive conditions was used. In silico docking, employing soft-soft (flexible) docking procedure was used to study the interactions of AAI with the active sites of these human enzymes. RESULTS: The predicted binding free energies and distances between an AAI ligand and a heme cofactor are similar for all CYPs evaluated. AAI also binds to the active sites of CYP1A1, 1A2 and 1B1 in similar orientations. The carboxylic group of AAI is in the binding position situated directly above heme iron. This ligand orientation is in CYP1A1/1A2 further stabilized by two hydrogen bonds; one between an oxygen atom of the AAI nitro-group and the hydroxyl group of Ser122/Thr124; and the second bond between an oxygen atom of dioxolane ring of AAI and the hydroxyl group of Thr497/Thr498. For the CYP1B1:AAI complex, however, any hydrogen bonding of the nitro-group of AAI is prevented as Ser122/Thr124 residues are in CYP1B1 protein replaced by hydrophobic residue Ala133. CONCLUSION: The experimental observations indicate that CYP1B1 is more than 10× less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å.
- MeSH
- adukty DNA chemie metabolismus MeSH
- Aristolochia chemie MeSH
- aromatické hydroxylasy chemie genetika metabolismus MeSH
- chemické modely MeSH
- cytochrom P-450 CYP1A1 chemie genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 chemie genetika metabolismus MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- katalytická doména účinky léků MeSH
- kyseliny aristolochové škodlivé účinky chemie farmakokinetika MeSH
- léky rostlinné čínské škodlivé účinky chemie farmakokinetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- nemoci ledvin chemicky indukované MeSH
- nitroreduktasy škodlivé účinky chemie farmakokinetika MeSH
- počítačová simulace MeSH
- sekvence aminokyselin MeSH
- terciární struktura proteinů účinky léků MeSH
- vodíková vazba účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bioremediation processes based on biofilms are usually very effective. The presence of (bio)surfactants in such processes can increase bioavailability of hydrophobic pollutants in aqueous phase. However, surfactants can affect the biofilm as well as individual microbial cells in different ways. Biosurfactants produced by a microbial population can be involved in the final structure of biofilm. An external application of synthetic surfactants or 'foreign' biosurfactants often results in partial or complete destruction of the biofilm and their high concentrations also have a toxic effect on microbial cells. Finding a suitable surfactant and its concentration, which would minimize the negative effects mentioned above, would allow to construct effective bioremediation processes using the benefits of both the biofilm and the surfactant. In this context, G(+) bacterium Rhodococcus erythropolis, which has a wide potential for biodegradation of aromatic compounds, was studied. High surface hydrophobicity of its cells, given mainly by the presence of mycolic acids in the cell envelopes, allows formation of stable biofilms. Three synthetic surfactants (Spolapon AOS 146, Novanik 0633A, Tween 80) and rhamnolipid isolated from Pseudomonas aeruginosa were used. Changes in initial adhesion and biofilm formation caused by the surfactants were monitored in a flow cell equipped with hydrophilic/hydrophobic carriers and analyzed by image analysis.
- MeSH
- aromatické uhlovodíky metabolismus MeSH
- biodegradace účinky léků MeSH
- biofilmy účinky léků MeSH
- fenoly metabolismus MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- látky znečišťující životní prostředí metabolismus MeSH
- micely MeSH
- počet mikrobiálních kolonií MeSH
- polyethylen MeSH
- povrchově aktivní látky farmakologie MeSH
- reologie účinky léků MeSH
- Rhodococcus účinky léků růst a vývoj fyziologie MeSH
- techniky vsádkové kultivace MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
