Partitioning the loss in vancomycin binding affinity for D-Ala-D-Lac into lost H-bond and repulsive lone pair contributions.
The binding affinity of 4, which incorporates a methylene (CH2) in place of the key linking amide of Ac2-l-Lys-d-Ala-d-Ala, for vancomycin was compared with that of Ac2-l-Lys-d-Ala-d-Ala (3) and Ac2-l-Lys-d-Ala-d-Lac (5). The vancomycin affinity for 4 was approximately 10-fold less than that of 3, but 100-fold greater than that of 5. This suggests that the reduced binding affinity of 5 (4.1 kcal/mol) may be attributed to both the loss of a key H-bond (1.5 kcal/mol) and a destabilizing lone pair/lone pair electrostatic interaction introduced with the ester oxygen of 5 (2.6 kcal/mol) with the latter, not the H-bond, being responsible for the largest share of the 1000-fold reduction.
McComas
Casey C
CC
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Crowley
Brendan M
BM
Boger
Dale L
DL
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D007700:Kinetics; D007773:Lactates / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014640:Vancomycin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D007773:Lactates; D009842:Oligopeptides; C120521:lysyl-alanyl-lactate; C033530:N(alpha), N-(epsilon)-diacetyl-lysyl-alanyl-alanine; D014640:Vancomycin