Conformational analysis recognition

The recognition that short chain / -peptides can form regular secondary structures initially came from detailed conformational analysis of y9 -peptides 1 and 66 (which incorporates a central (2S,3S)-3-amino-2-methylbutanoic acid residue) by NMR in pyridine-d5 and CD3OH [10, 103, 164] and homooUgomers (as short as four residues) of trons-2-amino-cyclohexanecarboxyhc acid (trans-ACHC) (e.g. hex-amer 2 for the (S,S) series) by NMR and X-ray diffraction [6, 126, 159]. 

Combining 2D-NOESY and 2D-ROESY NMR experiments with molecular modelling protocols, Kuhn and Kunz32 have been able to study the saccharide-induced peptide conformational behaviour of the recognition region of Ll-Cadherin. The detailed conformational analysis of this key biomolecule not only proves that the saccharide side chain exerts a marked influence on the conformation of the peptide chain, but also that the size and type of the saccharide indeed strongly affects the conformation of the main chain. 

DeFrees, S., Kosch, W., Way, W., Paulson, J., Sabesan, S., Halcomb, R., etal. (1995) Ligand recognition by E-selectin Synthesis, inhibitory activity and conformational analysis of bivalent sialyl Lewis x analogs. J. Am. Chem. Soc., 117, 66-79. 

Allen, F. H., Doyle, M. J., and Taylor, R. / Automated conformational analysis from crystallographic data. 1. A symmetry-modified single-linkage clustering algorithm for three-dimensional pattern recognition. Acta Cryst. B47, 29-40 (1991). 

Grassy, G. and Lahana, R. (1993). Statistical Analysis and Shape Recognition Applications to MD Simulations, Conformational Analysis and Structure-Activity Relationships. In Trends in QSAR and Molecular Modelling 92 (Wermuth, C.G., ed.), ESCOM, Leiden (The Netherlands), pp. 216-219. 

Wu, L. Li, Y., Study on the recognition of templates and their analogues on molecularly imprinted polymer using computational and conformational analysis approaches, J. Mol. Recognit. 2004, 17, 567-574... 

Lam, P.Y.S. et al. Cyclic HIV protease inhibitors Synthesis, conformational analysis, P2/P2 structure-activity relationship, and molecular recognition of cyclic ureas. J. Med. Chem. 1996, 39, 3514-3525. 

In summary, our conformational analysis of carnitine and acetylcarnitine shows that carnitine prefers extended ov a g and acetylcarnitine folded ov g g. The important points for inhibitor design are that the C3—C4 bond has a strong preference for and the C2—C3 bond is equally populated in either the a or g conformation. We can lock the C3—C4 bond in this conformation by formation of a ring and not lose much in recognition. We are less certain as to whether or not to lock the conformation of the C2—C3 bond. 

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