2brh: Difference between revisions

Revision as of 17:40, 21 February 2008

STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY

OverviewOverview

We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.

About this StructureAbout this Structure

2BRH is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity., Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE, J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:15974586

Page seeded by OCA on Thu Feb 21 16:40:49 2008

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OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-We report the discovery, synthesis, and crystallographic binding mode of, novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1, kinase, an oncology target. These inhibitors are synthetically tractable, and inhibit Chk1 by competing for its ATP site. A chronological account, allows an objective comparison of modeled compound docking modes to the, subsequently obtained crystal structures. The comparison provides insights, regarding the interpretation of modeling results, in relationship to the, multiple reasonable docking modes which may be obtained in a kinase-ATP, site. The crystal structures were used to guide medicinal chemistry, efforts. This led to a thorough characterization of a pair of, ligand-protein complexes which differ by a single hydrogen bond. An, analysis indicates that this hydrogen bond is expected to contribute a, fraction of the 10-fold change in binding affinity, adding a valuable, observation to the debate about the energetic role of hydrogen bonding in, molecular recognition.
+We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.
 ==About this Structure==
@@ Line 13: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Transferred entry: 2.7.11.1]]
+[[Category: Transferred entry: 2 7.11 1]]
-[[Category: Fisher, L.M.]]
+[[Category: Fisher, L M.]]
 [[Category: Foloppe, N.]]
 [[Category: Howes, R.]]
 [[Category: Kierstan, P.]]
 [[Category: Potter, A.]]
-[[Category: Robertson, A.G.S.]]
+[[Category: Robertson, A G.S.]]
-[[Category: Surgenor, A.E.]]
+[[Category: Surgenor, A E.]]
 [[Category: DFW]]
 [[Category: atp-binding]]
@@ Line 37: / Line 37: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:27:04 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:40:49 2008''