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PDBsum entry 2r3h
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References listed in PDB file
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Key reference
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Title
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Structure-Guided discovery of cyclin-Dependent kinase inhibitors.
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Authors
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T.O.Fischmann,
A.Hruza,
J.S.Duca,
L.Ramanathan,
T.Mayhood,
W.T.Windsor,
H.V.Le,
T.J.Guzi,
M.P.Dwyer,
K.Paruch,
R.J.Doll,
E.Lees,
D.Parry,
W.Seghezzi,
V.Madison.
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Ref.
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Biopolymers, 2008,
89,
372-379.
[DOI no: ]
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PubMed id
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Abstract
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CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines
and imidazopyrazines were discovered through high-throughput screening. Crystal
structures of inhibitors with these bicyclic cores and two more related ones
show that all but one have a common binding mode featuring two hydrogen bonds
(H-bonds) to the backbone of the kinase hinge region. Even though ab initio
computations indicated that the imidazopyrazine core would bind more tightly to
the hinge, pyrazolopyrimidines gain an advantage in potency through
participation of N4 in an H-bond network involving two catalytic residues and
bridging water molecules. Further insight into inhibitor/CDK2 interactions was
gained from analysis of additional crystal structures. Significant gains in
potency were obtained by optimizing the fit of hydrophobic substituents to the
gatekeeper region of the ATP binding site. The most potent inhibitors have good
selectivity.
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