Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis

Chirality
Giulio VistoliB Testa

Abstract

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. A series of 20 dipeptides of general structure NH(2)-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1), pK(2) and pK(3)) and lipophilicity parameters (log P(N) and log D(7.4)) 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 P(MLP), 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). 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 function...Continue Reading

References

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Citations

Jun 25, 2013·European Journal of Medicinal Chemistry·Giulio VistoliGiancarlo Aldini
Jul 23, 2013·PLoS Computational Biology·Drazen PetrovBojan Zagrovic
Jun 1, 2014·International Journal of Molecular Sciences·Andrea PoloFrancesca Cappitelli
Sep 23, 2014·Chemistry & Biodiversity·Bernard TestaAlessandro Pedretti
Apr 8, 2016·Physical Chemistry Chemical Physics : PCCP·S SastreJ Frau
Oct 19, 2013·Physiological Reviews·Alexander A BoldyrevWim Derave
Jun 3, 2018·Amino Acids·Ramin Ghodsi, Sorayya Kheirouri

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