title: Vancomycin analogs: Seeking improved binding of d-Ala-d-Ala and d-Ala-d-Lac peptides by side-chain and backbone modifications.
abstract: 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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States.
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: 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
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D014640:Vancomycin