Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature.
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.
Salsi
Enea
E
Department of Biochemistry and Molecular Biology, University of Parma, Italy. andrea.mozzarelli@unipr.it
Bayden
Alexander S
AS
Spyrakis
Francesca
F
Amadasi
Alessio
A
Campanini
Barbara
B
Bettati
Stefano
S
Dodatko
Tetyana
T
Cozzini
Pietro
P
Kellogg
Glen E
GE
Cook
Paul F
PF
Roderick
Steven L
SL
Mozzarelli
Andrea
A
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
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D003547:Cysteine Synthase