ACE and density functional theory were employed to study the noncovalent interactions of cyclic decapeptide glycine-6-antamanide ([Gly6]AA), synthetic derivative of native antamanide (AA) peptide from the deadly poisonous fungus Amanita phalloides, with small cations (Li+, Rb+, Cs+, NH4+, and Ca2+) in methanol. The strength of these interactions was quantified by the apparent stability constants of the appropriate complexes determined by ACE. The stability constants were calculated using the nonlinear regression analysis of the dependence of the effective electrophoretic mobility of [Gly6]AA on the concentration of the above ions in the BGE (methanolic solution of 20 mM chloroacetic acid, 10 mM Tris, pHMeOH7.8, containing 0-70 mM concentrations of the above ions added in the form of chlorides). Prior to stability constant calculation, the effective mobilities measured at actual temperature inside the capillary and at variable ionic strength of the BGEs were corrected to the values corresponding to the reference temperature of 25°C and to the constant ionic strength of 10 mM. From the above ions, Rb+and Cs+cations interacted weakly with [Gly6]AA but no interactions of [Gly6]AA with univalent Li+and NH4+ions and divalent Ca2+ion were observed. The apparent stability constants of [Gly6]AA-Rb+and [Gly6]AA-Cs+complexes were found to be equal to 13 ± 4 and 22 ± 3 L/mol, respectively. The structural characteristics of these complexes, such as position of the Rb+and Cs+ions in the cavity of the [Gly6]AA molecule and the interatomic distances within these complexes, were obtained by the density functional theory calculations.
ACE in a free solution and quantum mechanical density functional theory have been applied to the investigation of interactions of glycine-6-antamanide ([Gly(6) ]AA), a synthetic derivative of cyclic decapeptide antamanide isolated from the highly poisonous mushroom Amanita phalloides, with sodium or potassium ions in methanol. First, from the dependence of effective electrophoretic mobility of [Gly(6) ]AA on Na(+) or K(+) ions concentration in the BGE (methanolic solution of 20 mM chloroacetic acid, 10 mM Tris, pHMeOH 7.8, containing 0-50 mM NaCl or 0-40 mM KCl), the apparent binding (stability) constants of [Gly(6) ]AA-Na(+) and [Gly(6) ]AA-K(+) complexes were evaluated as 26 ± 1 and 14 ± 1 L/mol, respectively. The employed ACE method included correction of the effective mobilities measured at ambient temperature and at variable ionic strength of the BGEs to the mobilities related to the reference temperature 25°C and to the constant ionic strength 10 mM. Second, the interaction energies of the [Gly(6) ]AA-Na(+) and [Gly(6) ]AA-K(+) complexes (-466.3 and -345.2 kJ/mol, respectively) and the structural details of these complexes, such as position of the Na(+) and K(+) ions in the cavity of the [Gly(6) ]AA molecule and the interatomic distances within these complexes, were determined by the density functional theory calculations.
A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- akridiny chemie MeSH
- aktivace enzymů účinky léků MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- piperaziny chemie MeSH
- takrin chemie MeSH
- thiomočovina chemie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A regioselective synthesis of 3-alkyl-2-[(anthracen-9-yl)imino]thiazolidin-4-ones 2a-2e and 2-(alkylimino)-3-(anthracen-9-yl)thiazolidin-4-ones 3a-3e from appropriate thioureas using methyl bromoacetate or bromoacetyl bromide, respectively, has been rationalized by DFT calculations of model thiourea and its phenyl derivative. The proposed mechanism indicates that the regioselective formation of the target thiazolidinones is a consequence of a different reactivity of the reagents and a varying stability of the intermediates, 1-alkyl-3-(anthracen-9-yl)-2-[(methoxycarbonyl)methyl]isothioureas 4a-4e and 1-alkyl-3-(anthracen-9-yl)-2-(bromoacetyl)isothioureas 6a-6e.
