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Assessment of inhibitors of S‐adenosylmethionine synthesis discovered by computational docking
Author(s) -
Taylor John C,
Markham George D
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a896-c
Subject(s) - docking (animal) , in vivo , biochemistry , enzyme , in vitro , escherichia coli , active site , isozyme , biology , virtual screening , gene isoform , chemistry , drug discovery , gene , genetics , medicine , nursing
S‐Adenosylmethionine (AdoMet) is the predominant alkylating agent in all cells. The only known biosynthetic route to AdoMet is the reaction of ATP and L‐methionine, which is catalyzed by S‐adenosylmethionine synthetase. Most bacterial and eucaryotic AdoMet synthetases are highly conserved in sequence and structure, with eucaryotes possessing two subtly different isozymes. The multitude of essential metabolic roles of AdoMet, its involvement in the modulation of cell growth, and the change of the synthetase isoform present in mammalian liver tumors, has led to a decades long search for inhibitors with in vitro and in vivo utility. We report results from an initial virtual screening to assess the more than 180,000 known compounds to look for potential ligands to the crystallographically defined active site of the Escherichia coli enzyme. The computational docking program GLIDE™ from Schrodinger, LLC, was used. Candidate compounds identified from the computational screenings were further evaluated as inhibitors by in vitro enzyme assays and in vivo cell growth inhibition and AdoMet rescue experiments. Inhibitors with submicromolar affinity that are structurally unrelated to the natural ligands have been identified. Supported by NIH grant GM31186.