Design, synthesis and solution structure of a renin inhibitor Structural constraints from NOE, and homonuclear and heteronuclear coupling constants combined with distance geometry calculations

FEBS Letters

Repine, Joseph T.²  Reily, Michael D.²  Wagner, Gerhard¹  Humblet, Christine C.²  Thanabal, Venkataraman²  Lunney, Elizabeth A.² 

[1] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA;Chemistry Department, Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, USA

关键词: Renin inhibitor;    Solution structure;    Heteronuclear coupling constant;    Distance geometry;    Molecular modeling;    Drug design;    ROESY;    rotating frame nuclear Overhauser spectroscopy;    COSY;    correlated spectroscopy;    TOCSY;    total correlated spectroscopy;    AMPMA;    meta-di(aminomethyl)benzene;    BNMA;    bis-[(1-naphthyl)methyl]acetic acid;    BOC;    N-t-butyloxycarbonyl;    DCC;    1;    3-dicyclohexylcarbodiimide;    HOBT;    1-hydroxybenzotriazole hydrate;   

DOI  :  10.1016/0014-5793(92)80293-P

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

A macrocyclic renin inhibitor was designed using molecular modeling and a model of human renin. The synthesized molecule displayed poor binding affinity. To investigate the reasons for the observed inactivity, the structure of the compound has been studied by NMR spectroscopy and distance geometry. Structural constraints for distance geometry calculations were derived from nuclear Overhauser effects and homonuclear and heteronuclear three bond coupling constants. Homonuclear coupling constants were measured directly from the resolution-enhanced proton spectra and heteronuclear coupling constants were measured from the natural abundance ¹⁵N- and ¹³C-edited TOCSY experiments. One φ angle was determined uniquely by this method and two were reduced to two possible values each. By using a statistical analysis of 400 structures generated with distance geometry, two families of structures were found to be consistent with the NMR data. The solution structures so derived were different from the originally designed structure, including an internal hydrogen bond. This provides a possible explanation for the lack of effectiveness of this compound.

【 授权许可】

Unknown