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PDBsum entry 3at4
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Transferase/transferase inhibitor
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PDB id
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3at4
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References listed in PDB file
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Key reference
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Title
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A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to ck2 kinase.
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Authors
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T.Kinoshita,
Y.Sekiguchi,
H.Fukada,
T.Nakaniwa,
T.Tada,
S.Nakamura,
K.Kitaura,
H.Ohno,
Y.Suzuki,
A.Hirasawa,
I.Nakanishi,
G.Tsujimoto.
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Ref.
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Mol Cell Biochem, 2011,
356,
97.
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PubMed id
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Abstract
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The detailed understanding of the molecular features of a ligand binding to a
target protein, facilitates the successful design of potent and selective
inhibitors. We present a case study of ATP-competitive kinase inhibitors that
include a pyradine moiety. These compounds have similar chemical structure,
except for distinct terminal hydrophobic cyclopentyl or isopropyl groups, and
block kinase activity of casein kinase 2 subunit α (CK2α), which is a target
for several diseases, such as cancer and glomerulonephritis. Although these
compounds display similar inhibitory potency against CK2α, the crystal
structures reveal that the cyclopentyl derivative gains more favorable
interactions compared with the isopropyl derivative, because of the additional
ethylene moiety. The structural observations and biological data are consistent
with the thermodynamic profiles of these inhibitors in binding to CK2α,
revealing that the enthalpic advantage of the cyclopentyl derivative is
accompanied with a lower entropic loss. Computational analyses indicated that
the relative enthalpic gain of the cyclopentyl derivative arises from an
enhancement of a wide range of van der Waals interactions from the whole
complex. Conversely, the relative entropy loss of the cyclopentyl derivative
arises from a decrease in the molecular fluctuation and higher conformational
restriction in the active site of CK2α. These structural insights, in
combination with thermodynamic and computational observations, should be helpful
in developing potent and selective CK2α inhibitors.
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