Molecular Pharmacology, Vol 11, 126-132, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

A Structure-Activity Study by Nuclear Magnetic Resonance of Peptide Interactions with Vancomycin

¹ Division of Molecular Pharmacology, National Institute for Medical Research, Mill Hill, London, N.W. 7, England

The interaction of vancomycin with peptides related to acetyl-D-alanyl-D-alanine has been examined by measuring the chemical shifts of all measurable protons on the peptide when they form complexes with vancomycin. The objective was to test whether alterations of the structures of neighboring groups are reflected in the interactions of an unchanged index group. In general this is so, the COOH-terminal alanine group showing least perturbation and the NH₂-terminal acetyl group showing the largest changes. The lability of the chemical shifts is a reasonable indicator of the contribution of the parts of the molecule to the over-all binding energy of the complex. When the structure of the ligand is changed, its topological relationship to the binding site changes so as to achieve a free-energy minimum. This makes linear addition of group free-energy components only an approximation.

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ACKNOWLEDGMENT We are grateful to Lilly Research Centre, Ltd., for a generous supply of vancomycin hydrochloride.