2BRG
Structure-based Design of Novel Chk1 Inhibitors: Insights into Hydrogen Bonding and Protein-Ligand Affinity
Summary for 2BRG
| Entry DOI | 10.2210/pdb2brg/pdb |
| Related | 1IA8 1NVQ 1NVR 1NVS 2BR1 2BRB |
| Descriptor | SERINE/THREONINE-PROTEIN KINASE CHK1, (5,6-DIPHENYL-FURO[2,3-D]PYRIMIDIN-4-YLAMINO)-ACETIC (3 entities in total) |
| Functional Keywords | drug design, furanopyrimidine, molecular recognition, oncology, pyrrolopyrimidine, atp-binding, cell cycle, dna damage, kinase, nuclear protein, phosphorylation, polymorphism, serine/threonine-protein kinase, transferase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 34493.54 |
| Authors | Foloppe, N.,Fisher, L.M.,Howes, R.,Kierstan, P.,Potter, A.,Robertson, A.G.S.,Surgenor, A.E. (deposition date: 2005-05-05, release date: 2005-05-12, Last modification date: 2023-12-13) |
| Primary citation | Foloppe, N.,Fisher, L.M.,Howes, R.,Kierstan, P.,Potter, A.,Robertson, A.G.S.,Surgenor, A.E. Structure-Based Design of Novel Chk1 Inhibitors: Insights Into Hydrogen Bonding and Protein-Ligand Affinity. J.Med.Chem., 48:4332-, 2005 Cited by PubMed Abstract: 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. PubMed: 15974586DOI: 10.1021/JM049022C PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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