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Updated: Jun 26, 2026

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Vancomycin resistance: modeling backbone variants with D-Ala-D-Ala and D-Ala-D-Lac peptides
Siegfried S F Leung1, Julian Tirado-Rives, William L Jorgensen
1Department of Chemistry, Yale University, New Haven, 225 Prospect Street, CT 06520-8107, USA.
Abstract:
To seek vancomycin analogs with broader antibacterial activity, effects of backbone modifications for the agylcon 2 on binding with D-Ala-D-Ala- and D-Ala-D-Lac-containing peptides were investigated by Monte Carlo/free energy perturbation (MC/FEP) calculations. The experimental trend in binding affinities for 2 with three tripeptides was well reproduced. Possible modifications of the peptide bond between residues 4 and 5 were then considered, specifically for conversion of the OCNH linkage to CH(2)NH(2)(+) (6), FCCH (7), HCCH (8), and HNCO (9). The MC/FEP results did not yield binding improvements for 7, 8, and 9, though the fluorovinyl replacement is relatively benign. The previously reported analog 6 remains as the only variant that exhibits improved affinity for the D-Ala-D-Lac sequence and acceptable affinity for the D-Ala-D-Ala sequence.
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