2BR1

Structure-based Design of Novel Chk1 Inhibitors: Insights into Hydrogen Bonding and Protein-Ligand Affinity

2BR1 の概要

• エントリーDOI: 10.2210/pdb2br1/pdb
• 関連するPDBエントリー: 1IA8 1NVQ 1NVR 1NVS 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO
• 分子名称: SERINE/THREONINE-PROTEIN KINASE CHK1, 2-[5,6-BIS-(4-METHOXY-PHENYL)-FURO[2,3-D]PYRIMIDIN-4-YLAMINO]-ETHANOL, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, drug design, furanopyrimidine, molecular recognition, oncology, pyrrolopyrimidine, kinase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34731.69

構造登録者

Foloppe, N.,Fisher, L.M.,Howes, R.,Kierstan, P.,Potter, A.,Robertson, A.G.S.,Surgenor, A.E. (登録日: 2005-04-29, 公開日: 2005-05-12, 最終更新日: 2023-12-13)

主引用文献

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

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: 15974586
DOI: 10.1021/JM049022C

実験手法

X-RAY DIFFRACTION (2 Å)