Importance Of The Hydrophobic Energy: Structural Determination Of A Hypoglycemic Drug Of The Meglitinide Family By Nuclear Magnetic Resonance And Molecular Modeling
[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.
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
1. Malaisse WJ, Stimulation of insulin release by non-sulfonylurea hypoglycemic agents: the meglitinide family. Horm Metab Res 27: 263-266, 1995.
2. Malaisse WJ and Sato F, Insulinotropic aciton of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate. I. Secretory and cationic aspects. Gen Pharmacol 26: 1313-1316, 1995.
3. Malaisse WJ, Insulinotropic action of meglitinide analogs: modulation by an activator of ATP-sensitive K+ channels and high extracellular K+ concentrations. Pharmacol Res, in press.
4. Lins L, Brasseur R and Malaisse WJ, Conformation analysis of non-sulfonylurea hypoglycemic agents of the meglitinide family. Biochem Pharmacol 50: 1879-1884, 1995.
5. Bax A, Griffey RH and Hawkins BL, Correlation of proton and nitrogen-15 chemical shifts by multiple quantum NMR. J Magn Reson 55: 301-315, 1983.
6. Bax A and Summers MF, 1H and 13C assignments from sensitivity enhanced detection of heteronuclear multiple bond connectivity by 2D multiple quantum NMR. J Am Chem Soc 108: 2093-2094, 1986.
7. Griesinger C, Sørensen OW and Ernst RR, Practical aspects of the E.COSY technique. Measurements of scalar spin-spin coupling constants in peptides. J Magn Reson 75: 474-492, 1987.
8. Macura S and Ernst RR, Elucidation of cross relaxation in liquids by two-dimensional NMR spectroscopy. Mol Phys 41: 95-117, 1980.
9. Marion D and Wüthrich K, Application of phase sensitive two dimensional correlated spectroscopy (COSY) for measurements of 1H-1H spin-spin coupling constants in proteins. Biochim Biophys Res Commun 113: 967-974, 1983.
10. Neuhaus D and Williamson MP, The Nuclear Overhauser Effect in Structural and Conformational Analysis. VCH, New York, 1989.
11. Andersen NH, Eaton HL and Lai X, Quantitative small molecule NOESY. A practical guide for derivation of cross-relaxation rates and internuclear distances. Magn Reson Chem 27: 515-528, 1989.
12. Allinger NL, Conformational analysis. 130. MM2. A hydrocarbon force field utilizing V1 and V2 torsional terms. J Am Chem Soc 99: 8127-8134, 1977.
13. Brasseur R and Deleers M, Conformational analysis of 6-cis and 6-trans leukotrienes-B4-Ca2+ complexes. Proc Natl Acad Sci USA 81: 3370, 1984.
14. Lins L and Brasseur R, The hydrophobic effect in protein folding. FASEB J 9: 535-540, 1995.
15. Brasseur R, Simulating the folding of small proteins using the local minimum energy and the free solvation energy yields native-like structures. J Mol Graphics 13: 312-322, 1995.
16. Nelder JA and Mead R, A simplex method for function minimization. Computer J 7: 308-313, 1965.
17. Rahman M and Brasseur R, WinMGM: a fast CPK molecular graphics program for analyzing molecular structure. J Mol Graphics 12: 212-218, 1994.
18. Brasseur R (Ed.), TAMMO: Theoretical Analysis of Membrane Molecular Organization. In Molecular Description of Biological Membranes by Computer-Aided Conformational Analysis, vol. 1. CRC Press, Boca Raton, 1990.
19. Waldburger CD, Schildbach JF and Sauer RT, Are buried salt bridges important for protein stability and conformational specificity? Nature Struct Biol 2: 122-128, 1995.