2br1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==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 . | 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== | ==About this Structure== | ||
2BR1 is a | 2BR1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and PFP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BR1 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 33: | Line 33: | ||
[[Category: x-ray crystallography]] | [[Category: x-ray crystallography]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:28:04 2007'' | ||