Conformational analysis of 7-oxoacyl-L-alanyl-D-isoglutamines.
In a recent article (Planinsek, O., Srcic, S., 1999. Int. J. Pharm. 87, 199-207) some interesting physicochemical properties of a series N-(7-oxoacyl)-L-alanyl-D-isoglutamines with n=0-6 methylene groups between the terminal methyl and 7-oxo group were measured. In view of the practical importance of these N-acetylmuramyldipeptide(MDP) immunomodulator analogues and their interesting biological properties a detailed conformational analysis was undertaken for the series with n=3-6 methylene spacers between the 7-oxo and terminal methyl groups. The puzzle posed by the reversal of the measured water solubility and lipophylicity could be resolved by using the Monte Carlo approach to searching the conformational space of the molecules in this series. We have found that the increase in water solubility and drop in lipophylicity when the number of methylene groups is increased from 5 to 6 can be attributed to the change in predominant conformation in the conformational family as described by the Boltzmann distribution of conformations. Notwithstanding this, we point out the changes in biological response coupled to the nonlinearity of the physicochemical behaviour in the series.
Solmajer
T
T
Laboratory for Molecular Modeling and NMR, National Institute of Chemistry, and Lek, d.d., P.O. Box 3430, Hajdrihova 19, 1115, Ljubljana, Slovenia. tom.solmajer@ki.si
Planinsek
O
O
Srcic
S
S
D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D000465:Algorithms; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005973:Glutamine / Q000031:analogs & derivatives* / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D012995:Solubility; D013237:Stereoisomerism
D000276:Adjuvants, Immunologic; D008055:Lipids; D005973:Glutamine; C059858:isoglutamine; D000409:Alanine