2C3J

Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification

2C3J の概要

• エントリーDOI: 10.2210/pdb2c3j/pdb
• 関連するPDBエントリー: 1IA8 1NVQ 1NVR 1NVS 2BR1 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO 2C3K 2C3L
• 分子名称: SERINE/THREONINE-PROTEIN KINASE CHK1, DEBROMOHYMENIALDISINE, SULFITE ION, ... (4 entities in total)
• 機能のキーワード: drug design, molecular modeling, molecular recognition, oncology, transferase, cell cycle, dna damage, dna repair, atp-binding, kinase, nuclear protein, nucleotide-binding, phosphorylation, polymorphism, serine/threonine-protein kinase, ubl conjugation
• 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: 34473.45

構造登録者

Foloppe, N.,Fisher, L.M.,Francis, G.,Howes, R.,Kierstan, P.,Potter, A. (登録日: 2005-10-10, 公開日: 2005-11-23, 最終更新日: 2023-12-13)

主引用文献

Foloppe, N.,Fisher, L.M.,Francis, G.,Howes, R.,Kierstan, P.,Potter, A.
Identification of a Buried Pocket for Potent and Selective Inhibition of Chk1: Prediction and Verification.
Bioorg.Med.Chem., 14:1792-, 2006

PubMed Abstract: Inhibition of the Chk1 kinase by small molecules binding to its active site is a strategy of great therapeutic interest for oncology. We report how computational modelling predicted the binding mode of ligands of special interest to the Chk1 ATP site, for representatives of an indazole series and debromohymenialdisine. These binding modes were subsequently confirmed by X-ray crystallography. The binding mode of a potent indazole derivative involves non-conventional C-H...O and N-H...pi-aromatic interactions with the protein. These interactions are formed in a buried pocket at the periphery of the ATP-binding site, the importance of which has previously been overlooked for ligand design against Chk1. It is demonstrated that filling this pocket can confer ligands with dramatically enhanced affinity for Chk1. Structural arguments in conjunction with assay data explain why targeting this pocket is also advantageous for selective binding to Chk1. Structural overlays of known inhibitors complexed with Chk1 show that only the indazole series utilizes the pocket of interest. Therefore, the analysis presented here should prove helpful in guiding future structure-based ligand design efforts against Chk1.

PubMed: 16289938
DOI: 10.1016/J.BMC.2005.10.022

実験手法

X-RAY DIFFRACTION (2.1 Å)