Article (Scientific journals)
Importance Of The Hydrophobic Energy: Structural Determination Of A Hypoglycemic Drug Of The Meglitinide Family By Nuclear Magnetic Resonance And Molecular Modeling
Lins, Laurence; Brasseur, Robert; Malaisse, Wj. et al.
1996In Biochemical Pharmacology, 52 (8), p. 1155-1168
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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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lins, Laurence  ;  Université de Liège - ULiège > Gembloux Agro-Bio Tech
Brasseur, Robert ;  Université de Liège - ULiège > Gembloux Agro-Bio Tech
Malaisse, Wj.
Biesemans, M.
Verheyden, P.
Willem, R.
Language :
English
Title :
Importance Of The Hydrophobic Energy: Structural Determination Of A Hypoglycemic Drug Of The Meglitinide Family By Nuclear Magnetic Resonance And Molecular Modeling
Publication date :
1996
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
eISSN :
1873-2968
Publisher :
Elsevier, Netherlands
Volume :
52
Issue :
8
Pages :
1155-1168
1155-68
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 25 June 2010

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