- Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis
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Objectives: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. Methods: A series of 20 dipeptides of general structure NH2-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK1, pK2 and pK3) and lipophilicity parameters (log PN and log D7.4) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log PMLP, meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). Results: Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. Conclusion: This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression.
- Vistoli, Giulio,Straniero, Valentina,Pedretti, Alessandro,Fumagalli, Laura,Bolchi, Cristiano,Pallavicini, Marco,Valoti, Ermanno,Testa, Bernard
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p. 566 - 576
(2012/08/29)
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- Thermodynamic and (1)H NMR Study of Proton Complex Formation of Histidine-containing Cyclodipeptides in Aqueous Solution
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A thermodynamic and (1)H NMR study of proton complex formation in aqueous solution of some L-histidine-containing cyclic L-dipeptides has been carried out.The enthalpic and entropic changes associated with protonation of the cyclodipeptides, obtained by potentiometric and calorimetric measurements, together with the (1)H NMR data and NOESY experiments, enable the role played by non-covalent interactions in proton complex formation to be assessed.In addition, a comparison with c(Gly-His) permits the influence of side-chain residues on the conformation of protonated species to be observed.
- Arena, Giuseppe,Impellizzeri, Giuseppe,Maccarrone, Giuseppe,Pappalardo, Giuseppe,Sciotto, Domenico,Rizzarelli, Enrico
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p. 371 - 376
(2007/10/02)
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- Synthesis and Biological Activity of Angiotensin II Analogues Containing a Val-His Replacement, ValΨHis
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The dipeptide mimic ValΨHis (4) was incorporated into angiotensin II (AII) analogues to provide an octapeptide saralisn derivative (29) as well as tetrapeptide analogue 19.Three C-terminal tetrapeptides (21, 25, and 28) were also prepared.All
- Mohan, Raju,Chou, Yuo-Ling,Bihovsky, Ron,Lumma, William C.,Erhardt, Paul W.,Shaw, Kenneth J.
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p. 2402 - 2410
(2007/10/02)
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