Bovine trypsin is a model system for the serine protease class of enzymes, which
is an important target for contemporary medicinal chemistry. Some structural and
thermodynamic reports are available on its interaction with benzamidine-based
compounds but no structural information is available so far on its binding modes
to the active principles of the trypanocidal drugs Pentacarinate (pentamidine)
and Berenil (diminazene). The crystallographic structures of bovine beta-trypsin
in complex with the ligands were determined to a resolution of 1.57 A
(diminazene) and 1.70 A (diminazene and pentamidine). The second benzamidine
moieties in these inhibitors are bound to the enzyme in different hot spots and
only few hydrogen bonds mediate these interactions. Thermodynamic parameters for
the association of pentamidine with beta-trypsin reveal that this inhibitor has
about 1.3-fold lower affinity than diminazene. Moreover its binding mode
resembles other benzamidine-based compounds that assess the aryl binding pocket
of the enzyme; however, with almost 2.5-fold higher affinity. This is the first
structural evidence of the binding of Berenil and Pentacarinate active
principles trypanocidal drugs to serine proteases.
