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De Novo Design, Synthesis, and In Vitro Evaluation of Inhibitors for Prokaryotic tRNA‐Guanine Transglycosylase: A Dramatic Sulfur Effect on Binding Affinity
Author(s) -
Meyer Emmanuel A.,
Brenk Ruth,
Castellano Ronald K.,
Furler Maya,
Klebe Gerhard,
Diederich François
Publication year - 2002
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/1439-7633(20020301)3:2/3<250::aid-cbic250>3.0.co;2-j
Subject(s) - guanine , stereochemistry , chemistry , enzyme , biochemistry , substrate (aquarium) , transfer rna , binding site , nucleotide , biology , rna , gene , ecology
A lipophilic pocket at the tRNA‐guanine transglycosylase (TGT) enzyme active site was discovered and a substantial contribution to the substrate binding free energy was observed when this pocket was filled by apolar side chains. A family of new inhibitors of TGT was developed by employing the principles of molecular recognition and structure‐based de novo design, and shown to display up to submicromolar binding affinity. Two X‐ray structures of TGT–inhibitor complexes confirmed the binding mode predicted in the design stage. An exceptional ”point mutation” effect on binding affinity was observed upon substitution of X=CH 2 in 1 with O or S.