2brh

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spinqualitylabelsall models 2brh, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

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.

About this Structure

2BRH is a Single protein structure of sequence from Homo sapiens with DFW 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.

Reference

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

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