title: Vancomycin resistance: modeling backbone variants with D-Ala-D-Ala and D-Ala-D-Lac peptides.
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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, 225 Prospect Street, CT 06520-8107, USA.
authors.forename: Siegfried S F
authors.initials: SS
authors.lastname: Leung
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D007773:Lactates / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D007773:Lactates; D010455:Peptides; C078877:alanyllactate; C002956:alanylalanine; D000409:Alanine