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New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S 2 Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation
Author(s) -
Fustero Santos,
Rodrigo Vanessa,
SánchezRoselló María,
del Pozo Carlos,
Timoneda Joaquín,
Frizler Maxim,
Sisay Mihiret T.,
Bajorath Jürgen,
Calle Luis P.,
Cañada F. Javier,
JiménezBarbero Jesús,
Gütschow Michael
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201100113
Subject(s) - dipeptide , cathepsin b , chemistry , cathepsin , stereochemistry , amino acid , face (sociological concept) , biochemistry , combinatorial chemistry , computer science , enzyme , philosophy , linguistics
Fluor‐in or out? Based on β,β‐difluorinated cycloaliphatic amino acids, a library of new dipeptide nitriles was evaluated as human cathepsin inhibitors. The orientation of the fluorinated face relative to the protein structure of cathepsin B was elucidated by molecular modeling and NMR studies (see figure). For ( R )‐configured eutomers, the fluorine atoms are directed to the S 2 pocket, whereas in ( S )‐configured distomers, the fluorinated face is solvent‐exposed.