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PDBsum entry 2uue
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Transferase/inhibitor
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PDB id
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2uue
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References listed in PDB file
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Key reference
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Title
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Replace: a strategy for iterative design of cyclin-Binding groove inhibitors.
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Authors
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M.J.Andrews,
G.Kontopidis,
C.Mcinnes,
A.Plater,
L.Innes,
A.Cowan,
P.Jewsbury,
P.M.Fischer.
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Ref.
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Chembiochem, 2006,
7,
1909-1915.
[DOI no: ]
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PubMed id
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Abstract
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We describe a drug-design strategy termed REPLACE (REplacement with Partial
Ligand Alternatives through Computational Enrichment) in which nonpeptidic
surrogates for specific determinants of known peptide ligands are identified in
silico by using a core peptide-bound protein structure as a design anchor. In
the REPLACE application example, we present the effective replacement of two
critical binding motifs in a lead protein-protein interaction inhibitor
pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These
were identified through docking of fragment libraries into the volume of the
cyclin-binding groove of CDK2/cyclin A vacated through truncation of the
inhibitor peptide-binding determinants. Proof of concept for this strategy was
obtained through the generation of potent peptide-small-molecule hybrids and by
the confirmation of inhibitor-binding modes in X-ray crystal structures. This
method therefore allows nonpeptide fragments to be identified without the
requirement for a high-sensitivity binding assay and should be generally
applicable in replacing amino acids as individual residues or groups in peptide
inhibitors to generate pharmaceutically acceptable lead molecules.
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Secondary reference #1
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Title
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Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design.
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Authors
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G.Kontopidis,
C.Mcinnes,
S.R.Pandalaneni,
I.Mcnae,
D.Gibson,
M.Mezna,
M.Thomas,
G.Wood,
S.Wang,
M.D.Walkinshaw,
P.M.Fischer.
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Ref.
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Chem Biol, 2006,
13,
201-211.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2. Richardson Diagram of the Overlay of Active and
Inactive apo-CDK2
(A) Active apo-CDK2 is shown in yellow;
inactive apo-CDK2 is shown in blue. The differences in the
orientation of the N and C domains and in the large movement of
the T-loop upon cyclin binding can be observed upon overlay of
the active and inactive structures from residues 170–285.
(B) Electron density difference maps (2F[o] − 1F[c]) in the
ATP binding site of the CDK2/cyclin A/4 complex.
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Figure 3.
Figure 3. Crystal Structures of Ligands 1 and 4 Bound in
Active and Inactive CDK2
(A–C) The overlay shown is
residues 77–143 of the same inhibitor (yellow, active; blue,
inactive) and with the substituted aniline derivative 4 (yellow)
bound in (B) monomeric CDK2 (green) and (C) active (pink) CDK2.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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