Abstract :
[en] The molecular structure of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)
propionic acid (KAD-1229), a hypoglycemic drug of the meglitinide family, was
studied by nuclear magnetic resonance (NMR) and molecular modeling. The results
of the NMR experiments indicated that KAD-1229 existed in solution in the form of
two stable conformers of equal population, called KADI and KADII in this paper.
Three different molecular modelings were then applied: the classical molecular
dynamics using the commercial Biosym and Hyperchem softwares and the Prot+
program, which is not based on a dynamical study but on a systematic
conformational analysis of the molecule, which includes a term that allows the
estimation of the hydrophobic interaction. The modeling results showed the
following points. First, in contrast with classical molecular dynamics, which
uses restraints from two-dimensional nuclear Overhauser effect (NOE) data, the
Prot+ KAD structure provides conformations that support experimental NMR data
without any external intervention. In the structures in agreement with NMR data,
an important hydrophobic interaction between the phenyl cycle and the
perhydroisoindole ring of KAD is observed. This interaction, which seems to play
a role in the biological activity of the drug, is lost when no restraints are
considered in classical molecular dynamics. Second, the difference between KADI
and KADII arises mainly from slight distance geometric differences at the level
of the perhydroisoindole and the phenyl rings.
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