3iqi

Publication Abstract from PubMed

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.

Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature.,Salsi E, Bayden AS, Spyrakis F, Amadasi A, Campanini B, Bettati S, Dodatko T, Cozzini P, Kellogg GE, Cook PF, Roderick SL, Mozzarelli A J Med Chem. 2010 Jan 14;53(1):345-56. PMID:19928859^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.