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Figure 1.
Figure 1. Crystal structure of the pyrazole scaffold and its
derivatives in complex with PDE4B or PDE4D. (a) Crystal
structure of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl
ester (pyrazole no. 2) bound to PDE4D, showing the pyrazole ring
sandwiched in the hydrophobic clamp formed by F372 and I336. The
conserved H-bond, seen in all pyrazole derivative cocrystal
structures, between the NE2 atom of the invariant glutamine and
the carboxylate group, is shown. (b) The crystal structure of
3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester
(pyrazole no. 8) bound to PDE4D, showing the same interactions
as its parent compound, and thus validating the dimethyl
pyrazole as a scaffold. The dimethyl pyrazole is sandwiched by
F372 and I336 and the carbonyl oxygen forms an H-bond with Q369.
The ethoxy group is tucked into the Q1 pocket. (c) Crystal
structure of
3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid
ethyl ester (pyrazole no. 21) bound to PDE4B and PDE4D. The
carbon atoms of pyrazole no. 21 bound to PDE4B and PDE4D are
shown in green and yellow respectively. The NO[2] group at the
meta-position of the phenyl ring formed H-bonds with T345, D392
in PDE4B and the two water molecules coordinating Zn2+ (omitted
for clarity). (d) Crystal structure of
1-(2-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid
ethyl ester (pyrazole no. 20) bound to PDE4B. The
Cl-substitution at the ortho-position of the phenyl ring makes
several hydrophobic contacts with residues M347, L393 and F446.
(e) Crystal structure of
1-(4-amino-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid
ethyl ester (pyrazole no. 19) bound to PDE4D. The amine group
forms three H-bonds with three water molecules, two of which are
coordinated to Mg2+. However, this amine nitrogen is also in
close proximity to the carbon atom in M273 which results in
unfavorable interactions. (f) Crystal structure of
1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid
ethyl ester (pyrazole no. 17) bound to PDE4D. The methoxy-phenyl
group rotated 180° to point away from the di-metal ions to avoid
the repulsive interactions between the methoxy group and the
di-metal ions.
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