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Kinetic Studies of Potent Thiosemicarbazone Inhibitors of Cruzain
Author(s) -
Chen ShenEn,
Siles Rogelio E.,
Zhou Ming,
Arispe Wara Milenka,
Lee Hanna,
Pinney Kevin G.,
Trawick Mary Lynn
Publication year - 2007
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.21.5.a641-d
Subject(s) - chemistry , stereochemistry , cathepsin , trypanosoma cruzi , enzyme , cathepsin b , semicarbazone , chagas disease , active site , moiety , cathepsin l , biochemistry , biology , virology , parasite hosting , world wide web , computer science
Cruzain, a cathepsin L‐ and B‐like enzyme, is the major cysteine protease from Trypanosoma cruzi , the causative agent of Chagas' disease which is a major public health problem in Latin America. Previously, we reported a small library of thiosemicarbazone derivatives as inhibitors of cruzain. (Siles, R.; Chen, S‐E.; Zhou, M.; Pinney, K. G.; Trawick, M. L. Bioorg. & Med. Chem. Lett . 2006, 16 , –4409). Kinetic data from the two most active compounds in this series, a bromo substitutued α‐tetralone (IC 50 17 nM ), and a dibromobenzophenone (IC 50 24 nM ), fit the Williams‐Morrison equation which applies to reversible covalent inhibition as well as slow, tight binding. The K i values for the two inhibitors are 1.5 and 2.2 nM respectively. Modeling studies support the kinetic results and suggest that, in addition to favorable interaction energies resulting from binding of the tetralone and benzene rings in the S 2 pocket of the enzyme, the thiosemicarbazone moiety is in close proximity to the active site Cys25 thiolate of cruzain in the best inhibitors of this series. Several of the thiosemicarbazone compounds from the library inhibit cathepsin B but with a distinct specificity from that of cruzain and cathepsin L. The authors thank the Vice‐Provost for Research of Baylor University (MLT) and the Welch Foundation (Grant No. AA‐1278, KGP) for financial support.