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X. Liu et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2949–2952
known as FABP3) were also evaluated by the fluorescence binding
assay. Although h-FABP and a-FABP have a sequence identity of
64.4% and share a highly conserved functional domain, our data
showed that almost all of the designed inhibitors and
BMS309403 exhibited remarkable selectivity to a-FABP over h-
FABP (Table 1). For instance, compound 5d selectively bound to
a-FABP with a Ki value of 5.0 nM, while its binding apparent Ki va-
talent program of Chinese Academy of Sciences, and National Nat-
ural Science Foundation (Grant #30811120429, 3097063 and
90813033) for their financial support.
Supplementary data
Supplementary data associated with this article can be found, in
lue against h-FABP was about 4.2 lM. This might be due to the rel-
atively smaller hydrophobic groove in h-FABP as compared to a-
FABP. The increase in the number of three-dimensional conforma-
tions compromised the binding affinity since it causes spatial col-
lision with some larger residues (such as Tyr115, Tyr117 and
Phe16), and hinders the formation of hydrogen bonds between
key carboxyl pharmacophore with residues Phe16 and Arg126 on
h-FABP as well (Supplementary data). Noticeably, when the car-
boxyl was substituted with dimethyl groups (compound 5g), the
biochemical activity against h-FABP was almost completely abol-
ished due to the unavoidable spatial collision caused by the rigidity
of the side chains.
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Acknowledgments
We thank National Basic Research Program of China (Grant
#2010CB529706, 2010CB9455000 and 2009CB940904), the 100-