title: Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature.
abstract: The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been proposed to be relevant for the development of antibiotics. Haemophilus influenzae O-acetylserine sulfhydrylase (OASS), catalyzing l-cysteine formation, is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine acetyltransferase into the active site. Four-hundred MNXXI pentapeptides were generated in silico, docked into OASS active site using GOLD, and scored with HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or Asp at position P4 and, to a lesser extent, at position P3 also significantly contribute to the binding interaction. The predicted affinity of 14 selected pentapeptides correlated well with the experimentally determined dissociation constants. The X-ray structure of three high affinity pentapeptide-OASS complexes were compared with the docked poses. These results, combined with a GRID analysis of the active site, allowed us to define a pharmacophoric scaffold for the design of peptidomimetic inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Parma, Italy. andrea.mozzarelli@unipr.it
authors.forename: Enea
authors.initials: E
authors.lastname: Salsi
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Bayden
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Alessio
authors.initials: A
authors.lastname: Amadasi
authors.forename: Barbara
authors.initials: B
authors.lastname: Campanini
authors.forename: Stefano
authors.initials: S
authors.lastname: Bettati
authors.forename: Tetyana
authors.initials: T
authors.lastname: Dodatko
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: Paul F
authors.initials: PF
authors.lastname: Cook
authors.forename: Steven L
authors.initials: SL
authors.lastname: Roderick
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D020134:Catalytic Domain; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003547:Cysteine Synthase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000201:enzymology; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D003547:Cysteine Synthase