Enthalpy
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Baricitinib is a drug used for the treatment of rheumatoid arthritis. It is a selective and reversible inhibitor of Janus kinases 1 and 2, which play an important role in signalling the pro-inflammatory pathway activated in autoimmune disorders such as rheumatoid arthritis. The pH-spectrophotometric and pH-potentiometric titrations allowed the measurement of three or four successive dissociation constants of Baricitinib. Baricitinib neutral LH2 molecule was able to protonate into two soluble cations LH42+, LH3+ and dissociate into two soluble anions LH- and L2- in pure water. The graph of molar absorption coefficients of differently protonated species versus wavelength indicated that the spectra εL, εLH, εLH2 were the nearly the same for these species and that the spectra εLH4 and εLH3 were also similar. In the pH range from 2-13, four pKa´s of spectra analysis were reliably estimated by REACTLAB at I =0.0020 mol. dm-3 values pKTa1 = 3.07, pKTa2 = 3.87, pKTa3 = 6.27, pKTa4 = 12.78 at 25 °C and pKTa1 = 3.00, pKTa2 = 3.79, pKTa3 = 6.12, pKTa4 = 12.75 at 37 °C. Potentiometric pH-titration analysis for a higher concentration of 1 × 10-3 mol. dm-3 estimated with ESAB at I =0.0001 mol. dm-3 values pKTa1 = 3.69, pKTa2 = 3.81, pKTa3 = 4.73 at 25 °C and pKTa1 = 3.62, pKTa2 = 3.73, pKTa3 = 4.43 at 37 °C. Molar enthalpy ΔH°, molar entropy ΔS° and Gibbs free energy ΔG° were calculated from the spectra using a dependence ln K to 1/T.
- MeSH
- azetidiny * MeSH
- entropie MeSH
- koncentrace vodíkových iontů MeSH
- puriny MeSH
- pyrazoly MeSH
- sulfonamidy MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
Kritická micelová koncentrácia lokálneho anestetika heptakaíniumchloridu v prostredí KBr (0,1 mol/l a 0,2 mol/l) bola určená spektrofotometricky v UV oblasti spektra v teplotnom intervale t =2 0–40 °C a pri pH ? 4,5–5,0. Závislosť CMC od teploty T mala tvar „U“ (U-shaped) s minimom pri teplote t = 25 °C. Parabolická závislosť CMC od teploty T bola fitovaním hodnôt charakterizovaná pomocou tzv. „power-law“ rovnice. Zo závislosti ln (CMC) od T sme fitovaním polynómom druhého stupňa získali parabolické rovnice pre jednotlivé koncentrácie študovanej látky, z ktorých boli pomocou modelu fázovej separácie vypočítané termodynamické parametre, ako sú: štandardná mólová Gibbsova energia (?G°), entalpia (?H°) a entropia (?S°). Z termodynamických parametrov bola ďalej určená tzv. „enthalpy-entropy“ kompenzácia pre študované prostredia. Kompenzačné teploty Tc sa pohybovali v rozmedzí (301 ± 1–303 ± 3) K. Napokon boli určené energetické príspevky entalpie (?H°) a entropie (–T?S°) k štandardnej mólovej Gibbsovej energii (?G°).
The critical micellar concentration (CMC) of the local anaesthetic agent heptacainium chloride in the solution of KBr was determined by the spectrophotometric method in the UV region of the spectrum at the temperature range of t = 20–40 °C and pH ? 4.5–5.0. The dependence of CMC on the temperature T turned out forming the U-shape with the minimum at the temperature of t = 25 °C. The parabolic dependence of CMC on the temperature T was drawn by the fitting of the values using the polynomial function and the so-called power law equation. The CMC dependence on the temperature T was fitted by the second degree polynomial function. The obtained parabolic equations were applied to the “phase separation model”, so the following thermodynamic parameters could be calculated: standard Gibbs free energy (?G°), enthalpy (?H°), and entropy (?S°). The thermodynamic parameters were further used to determine the so-called entropy-enthalpy compensation of the systems under study. The compensation temperature was in the following range: (301 ± 1–303 ± 3)K. Then the temperature dependence of the enthalpy (?H°) and entropy (–T?S°) contributions to the standard Gibbs free energy (?G°) for all prepared concentrations of the compound were calculated.
Combined effects of temperature and mobile phase on the reversed phase chromatographic behavior of alkylbenzenes and simple substituted benzenes were investigated on a Blaze C8 polydentate silica-based column, showing improved resistance against hydrolytic breakdown at temperatures higher than 60 degrees C, in comparison to silica-based stationary phases with single attachment sites. For better insight into the retention mechanism on polydentate columns, we determined the enthalpy and entropy of the transfer of the test compounds from the mobile to the stationary phase. The enthalpic contribution dominated the retention at 80% or lower concentrations of methanol in the mobile phase. Entropic effects are more significant in 90% methanol and in acetonitrile-water mobile phases. Anomalies in the effects of mobile phase on the enthalpy of retention of benzene, methylbenzene and polar benzene derivatives were observed, in comparison to regular change in enthalpy and entropy of adsorption with changing concentration of organic solvent and the alkyl length for higher alkylbenzenes. The temperature and the mobile phase effects on the retention are practically independent of each other and--to first approximation--can be described by a simple model equation, which can be used for optimization of separation conditions.
- MeSH
- acetonitrily chemie MeSH
- benzenové deriváty chemie MeSH
- chemické modely MeSH
- hydrofobní a hydrofilní interakce MeSH
- lineární modely MeSH
- methanol chemie MeSH
- reprodukovatelnost výsledků MeSH
- teplota MeSH
- termodynamika MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Specific conductivities of local anaesthetic 1-methoxy-3-(4-methylpiperazin-1-yl)propan-2-yl-4-propyl-oxyphenyl carbamate (LM9) in aqueous solution were measured as a function of the concentration and temperature. The critical micelle concentration, CMC, degree of ionization and the counterion binding of the micelle were estimated from the dependence of the specific conductivity measurements at various temperatures. The dependence of CMC on temperature was shown to be U-shaped with a minimum at the temperature T = 298.15 K. Thermodynamic parameters (Gibbs energy ΔG°, enthalpy ΔH°, entropy ΔS°) for the micelle system were estimated by applying the mass action model. Molecule LM9 exhibited the enthalpy-entropy compensation phenomenon. The compensation temperature Tc of the studied compound was 301.79 K.
Secondary structures of the G-rich strand of human telomere DNA fragments G3(TTAG3)n, n = 1-16, have been studied by means of circular dichroism spectroscopy and PAGE, in solutions of physiological potassium cation concentrations. It has been found that folding of these fragments into tetraplexes as well as tetraplex thermostabilities and enthalpy values depend on the number of TTAG3 repeats. The suggested topologies include, e.g. antiparallel and parallel bimolecular tetraplexes, an intramolecular antiparallel tetraplex, a tetraplex consisting of three parallel chains and one antiparallel chain, a poorly stable parallel intramolecular tetraplex, and both parallel and antiparallel tetramolecular tetraplexes. G3(TTAG3)3 folds into a single, stable and very compact intramolecular antiparallel tetraplex. With an increasing repeat number, the fragment tetraplexes surprisingly are ever less thermostable and their migration and enthalpy decrease indicate increasing irregularities or domain splitting in their arrangements. Reduced stability and different topology of lengthy telomeric tails could contribute to the stepwise telomere shortening process.
Entropy (ΔS), enthalpy (ΔH) and heat capacity (ΔCp) changes attending the oxytocin interaction with its two binding sites on myometrial cell membranes in sheep were derived from the temperature dependence of Kd values. The high affinity oxytocin site (Kd on the order of 10(-9)mol l(-1), 25 °C), ascribed to the oxytocin receptor (OXTR), is entropy-driven in the temperature range 0-37 °C. Enthalpy component prevails as a driving force in the binding to the low affinity site (Kd ≈ 10(-7)) within the higher temperature range. ΔCp values in both cases do not differ significantly from zero but become highly relevant in the presence of a GTP analog (10(-4)M GTP-γS). Under these conditions, ΔCp in the low site interaction becomes negative and ΔS is shifted toward negative values (enthalpy drift); ΔCp of the high affinity site rises to a high positive value and the interaction is even more strongly entropy driven. Atosiban, a competitive antagonist of oxytocin at OXTR displays a single significant binding site on myometrial cells (Kd about 10(-7)mol l(-1)). Thermodynamic profiles of atosiban and the low affinity oxytocin site show conspicuous similarities, indicating that the inhibitor is bound to the low affinity site, and not, with a lower affinity, to the putative receptor protein. It is suggested that the interaction of oxytocin with its responding system on myometrial membranes follows in two distinct steps that are likely to be associated with several independent binding domains in the GPCR receptor.
- MeSH
- arginin vasopresin metabolismus MeSH
- buněčná membrána metabolismus MeSH
- myometrium metabolismus MeSH
- ovce MeSH
- oxytocin metabolismus MeSH
- receptory oxytocinu metabolismus MeSH
- teplota MeSH
- termodynamika MeSH
- vasotocin analogy a deriváty metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Review article brings comprehensive survey on compounds having cooling taste (sensation) of both types, influencing the trigeminal perception and expressing negative enthalpy on dissolution. Other use of these compounds is discussed.
- MeSH
- chuť MeSH
- chuťová stimulancia MeSH
- čichová percepce MeSH
- lidé MeSH
- menthol chemie MeSH
- monoterpeny chemie MeSH
- potravní doplňky MeSH
- Check Tag
- lidé MeSH
A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.
- MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- kvantová teorie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The enantiomeric pairs of cis and trans stereoisomers of cyclic β-aminohydroxamic acids and their related cis and trans cyclic β-amino acids containing two chiral centers were directly separated on four structurally related chiral stationary phases derived from quinine and quinidine modified with (R,R)- and (S,S)-aminocyclohexanesulfonic acids. Applying these zwitterionic ion-exchangers as chiral selectors, the effects of the composition of the bulk solvent, the acid and base additives, the structures of the analytes, and temperature on the enantioresolution were investigated. To study the effects of temperature and obtain thermodynamic parameters, experiments were carried out at constant mobile phase compositions in the temperature range 5-50°C. The differences in the changes in standard enthalpy Δ(ΔH°), entropy Δ(ΔS°), and free energy Δ(ΔG°) were calculated from the linear van't Hoff plots derived from the ln α versus 1/T curves in the studied temperature range. Results thus obtained indicated enthalpy-driven separations in all cases. The sequence of elution of the enantiomers was determined and found to be reversed when ZWIX(-)™ was changed to ZWIX(+)™ or ZWIX(-A) to ZWIX(+A).
UNLABELLED: We report enzymologic, thermodynamic and structural analyses of a series of six clinically derived mutant HIV proteases (PR) resistant to darunavir. As many as 20 mutations in the resistant PRs decreased the binding affinity of darunavir by up to 13 000-fold, mostly because of a less favorable enthalpy of binding that was only partially compensated by the entropic contribution. X-ray structure analysis suggested that the drop in enthalpy of darunavir binding to resistant PR species was mostly the result of a decrease in the number of hydrogen bonds and a loosening of the fit between the inhibitor and the mutated enzymes. The favorable entropic contribution to darunavir binding to mutated PR variants correlated with a larger burial of the nonpolar solvent-accessible surface area upon inhibitor binding. We show that even very dramatic changes in the PR sequence leading to the loss of hydrogen bonds with the inhibitor could be partially compensated by the entropy contribution as a result of the burial of the larger nonpolar surface area of the mutated HIV PRs. DATABASE: Atomic coordinates and structure factors for the crystal structures PRwt-DRV and PRDRV2-DRV complex have been deposited in the Protein Data Bank under accession codes 4LL3 and 3TTP, respectively. STRUCTURED DIGITAL ABSTRACT: • PR and PR bind by x-ray crystallography (View interaction).
- MeSH
- HIV-proteasa chemie genetika metabolismus MeSH
- inhibitory HIV-proteasy chemie farmakologie MeSH
- molekulární sekvence - údaje MeSH
- mutace * MeSH
- sekvence aminokyselin MeSH
- simulace molekulového dockingu * MeSH
- sulfonamidy chemie farmakologie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- virová léková rezistence genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
