Vancomycin analogs: Seeking improved binding of d-Ala-d-Ala and d-Ala-d-Lac peptides by side-chain and backbone modifications.
In order to seek vancomycin analogs with improved performance against VanA and VanB resistant bacterial strains, extensive computational investigations have been performed to examine the effects of side-chain and backbone modifications. Changes in binding affinities for tripeptide cell-wall precursor mimics, Ac(2)-l-Lys-d-Ala-d-Ala (3) and Ac(2)-l-Lys-d-Ala-d-Lac (4), with vancomycin analogs were computed with Monte Carlo/free energy perturbation (MC/FEP) calculations. Replacements of the 3-hydroxyl group in residue 7 with small alkyl or alkoxy groups, which improve contacts with the methyl side chain of the ligands'd-Ala residue, are predicted to be the most promising to enhance binding for both ligands. The previously reported amine backbone modification as in 5 is shown to complement the hydrophobic modifications for binding monoacetylated tripeptides. In addition, replacement of the hydroxyl groups in residues 5 and 7 by fluorine is computed to have negligible impact on binding the tripeptides, though it may be pharmacologically advantageous.
Leung
Siegfried S F
SS
Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States.
Tirado-Rives
Julian
J
Jorgensen
William L
WL
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D008956:Models, Chemical; D008968:Molecular Conformation; D009010:Monte Carlo Method; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020713:Vancomycin Resistance
D000900:Anti-Bacterial Agents; D010455:Peptides; D014640:Vancomycin