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Fig. 9 (a) The inhibitors to lupin Ap 4 A hydrolase, where NSC51531, NSC232476, and
NSC89768 were identified by the virtual screen and NSC86169, NSC300513, and NSC401611
were structural analogs of NSC51531. (Reprinted with permission from [ 166 ], copyright 2009 by
the American Chemical Society). (b) A representation of the interaction between the three
sulfotyrosine groups of chemokine CXCL12 and the N-terminal region of the G-protein-coupled
receptor CXCR4. Virtual screening and NMR identified 3-(naphthalene-2-carbonylthiocarbo-
moylamino)benzoic acid (ZINC 310454) as a possible inhibitor of the binding between
CXCL12 and CXCR4, which was verified with a calcium flux assay. (Reprinted with permission
from [ 169 ], copyright 2010 by the American Chemical Society). (c) The docked pose of fragment
F152 ( magenta ) in the active site of human peroxiredoxin 5 with the hydroxyl groups oriented
towards catalytic cysteine (C47). (Reprinted with permission from [ 174 ], copyright 2010 by PLoS)
then screened using 2D 1 H- 15 N HSQCs, which showed that four of the compounds
bound weakly, but specifically, to CXCL12 in the region of interest. The strongest
binder, ZINC 310454, had a K D of ~64
M. Additional NMR screens with analogs
to ZINC 310454 showed the importance of the carboxylic acid and naphthyl group,
since analogs lacking these features showed no binding in the 2D 1 H- 15 N HSQC
experiments. Furthermore, a calcium flux assay demonstrated that 100
m
M ZINC
310454 inhibited CXCL12-mediated signaling. Correspondingly, ZINC 310454
may be a useful scaffold for drug development (Fig. 9b ). The results also reinforced
the validity of chemokines as a target for drug discovery.
Using molecular docking to screen a large compound library does reduce the
time and resources relative to an HTS assay, but it still suffers from an unfocused
approach. In general, virtual screens or HTS assays don't efficiently sample chemi-
cal space or improve the diversity of hits. Molecular modeling also requires a priori
knowledge of the binding site to guide the virtual screen, which may be difficult
when dealing with new potential therapeutic targets. One approach to these
problems may be to utilize NMR as the primary screening tool and molecular
m
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