Figure 1.
(a) The method involves linking a substrate-derived aldehyde
fragment to a library of aldehydes using bivalent oxyamine
linkers (n = 2–6). The tethering reactions are performed in
high-throughput and high-yield (>90%) using 96-well plates^5,
^6, ^7. Without the need for purification, the libraries are
directly screened against a desired enzyme target to rapidly
identify inhibitors. (b) Substrate fragment tethering using
6-formyluracil (11) as the substrate fragment yielded the first
small-molecule inhibitor of the DNA repair enzyme human UNG2
(13, K[d] = 6 M).
The interactions of the uracil and library fragments of dioxime
13 with human UNG2 are shown (Protein Data Bank ID 2HXM). The
tether does not directly interact with the enzyme and has an
unusual kinked conformation (see text).
The above figure is reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2009,
5,
407-413)
copyright 2009.
M).
The interactions of the uracil and library fragments of dioxime
13 with human UNG2 are shown (Protein Data Bank ID 2HXM). The
tether does not directly interact with the enzyme and has an
unusual kinked conformation (see text).