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 / E., Salsi; A., Bayden; Spyrakis, Francesca; A., Amadasi; Campanini, Barbara; Bettati, Stefano; Cozzini, Pietro; G. E., Kellogg; P. F., Cook; T., Dodatko; S. L., Roderick; Mozzarelli, Andrea. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:1(2010), pp. 345-356. [10.1021/jm901325e]

Design of O-acetylserine sulfhydrylase inhibitors by mimicking Nature.

SPYRAKIS, Francesca;CAMPANINI, Barbara;BETTATI, Stefano;COZZINI, Pietro;MOZZARELLI, Andrea
2010

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.
Design of O-acetylserine sulfhydrylase inhibitors by mimicking Nature / E., Salsi; A., Bayden; Spyrakis, Francesca; A., Amadasi; Campanini, Barbara; Bettati, Stefano; Cozzini, Pietro; G. E., Kellogg; P. F., Cook; T., Dodatko; S. L., Roderick; Mozzarelli, Andrea. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:1(2010), pp. 345-356. [10.1021/jm901325e]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2303851
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