title: Molecular dynamics simulation and linear interaction energy study of D-Glu-based inhibitors of the MurD ligase.
abstract: The biosynthetic pathway of the bacterial peptidoglycan, where MurD is an enzyme involved at the intracellular stage of its construction, represents a collection of highly selective macromolecular targets for novel antibacterial drug design. In this study as part of our investigation of the MurD bacterial target two recently discovered classes of the MurD ligase inhibitors were investigated resulting from the lead optimization phases of the N-sulfonamide D-Glu MurD inhibitors. Molecular dynamics simulations, based on novel structural data, in conjunction with the linear interaction energy (LIE) method suggested the transferability of our previously obtained LIE coefficients to further D-Glu based classes of MurD inhibitors. Analysis of the observed dynamical behavior of these compounds in the MurD active site was supported by static drug design techniques. These results complement the current knowledge of the MurD inhibitory mechanism and provide valuable support for the D-Glu paradigm of the inhibitor design.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia, andrej.perdih@ki.si.
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D056004:Molecular Dynamics Simulation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D018698:Glutamic Acid; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase