title: Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis.
abstract: OBJECTIVE
  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 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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Facoltà di Farmacia, Università degli Studi di Milano, Milano, Italy. Giulio.Vistoli@unimi.it
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
mesh_terms: D055598:Chemical Phenomena; D004151:Dipeptides / Q000737:chemistry*; D006639:Histidine; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D006639:Histidine