2cgx
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Inhibition of the Chk1 kinase by small molecules is of great therapeutic | + | Inhibition of the Chk1 kinase by small molecules is of great therapeutic interest for oncology and in understanding the cellular regulation of the G2/M checkpoint. We report how computational docking of a large electronic catalogue of compounds to an X-ray structure of the Chk1 ATP-binding site allowed prioritisation of a small subset of these compounds for assay. This led to the discovery of 10 novel Chk1 inhibitors, distributed among nine new and clearly different chemical scaffolds. Several of these scaffolds have promising lead-like properties. All these ligands act by competitive binding to the targeted ATP site. The crystal structures of four of these compounds bound to this site are presented, and reasonable modelled docking modes are suggested for the 5 other scaffolds. This structural context is used to assess the potential of these scaffolds for further medicinal chemistry efforts, suggesting that several of them could be elaborated to make additional interactions with the buried part of the ATP site. Some unusual interactions with the conserved kinase backbone motif are pointed out. The ligand-binding modes are also used to discuss their medicinal chemistry potential with respect to undesirable chemical functionalities, whether these functionalities bind directly to the protein or not. Overall, this work illustrates how virtual screening can identify a diverse set of ligands which bind to the targeted site. The structural models for these ligands in the Chk1 ATP-binding site will facilitate further medicinal chemistry efforts targeting this kinase. |
==About this Structure== | ==About this Structure== | ||
| Line 13: | Line 13: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 | + | [[Category: Transferred entry: 2 7.11 1]] |
| - | [[Category: Fisher, L | + | [[Category: Fisher, L M.]] |
[[Category: Foloppe, N.]] | [[Category: Foloppe, N.]] | ||
[[Category: Howes, R.]] | [[Category: Howes, R.]] | ||
[[Category: Potter, A.]] | [[Category: Potter, A.]] | ||
| - | [[Category: Robertson, A | + | [[Category: Robertson, A G.S.]] |
| - | [[Category: Surgenor, A | + | [[Category: Surgenor, A E.]] |
[[Category: 3D3]] | [[Category: 3D3]] | ||
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
| Line 38: | Line 38: | ||
[[Category: virtual screening]] | [[Category: virtual screening]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:48:31 2008'' |
Revision as of 14:48, 21 February 2008
|
IDENTIFICATION OF CHEMICALLY DIVERSE CHK1 INHIBITORS BY RECEPTOR-BASED VIRTUAL SCREENING
Overview
Inhibition of the Chk1 kinase by small molecules is of great therapeutic interest for oncology and in understanding the cellular regulation of the G2/M checkpoint. We report how computational docking of a large electronic catalogue of compounds to an X-ray structure of the Chk1 ATP-binding site allowed prioritisation of a small subset of these compounds for assay. This led to the discovery of 10 novel Chk1 inhibitors, distributed among nine new and clearly different chemical scaffolds. Several of these scaffolds have promising lead-like properties. All these ligands act by competitive binding to the targeted ATP site. The crystal structures of four of these compounds bound to this site are presented, and reasonable modelled docking modes are suggested for the 5 other scaffolds. This structural context is used to assess the potential of these scaffolds for further medicinal chemistry efforts, suggesting that several of them could be elaborated to make additional interactions with the buried part of the ATP site. Some unusual interactions with the conserved kinase backbone motif are pointed out. The ligand-binding modes are also used to discuss their medicinal chemistry potential with respect to undesirable chemical functionalities, whether these functionalities bind directly to the protein or not. Overall, this work illustrates how virtual screening can identify a diverse set of ligands which bind to the targeted site. The structural models for these ligands in the Chk1 ATP-binding site will facilitate further medicinal chemistry efforts targeting this kinase.
About this Structure
2CGX is a Single protein structure of sequence from Homo sapiens with 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
Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening., Foloppe N, Fisher LM, Howes R, Potter A, Robertson AG, Surgenor AE, Bioorg Med Chem. 2006 Jul 15;14(14):4792-802. Epub 2006 Mar 29. PMID:16574416
Page seeded by OCA on Thu Feb 21 16:48:31 2008
Categories: Homo sapiens | Single protein | Transferred entry: 2 7.11 1 | Fisher, L M. | Foloppe, N. | Howes, R. | Potter, A. | Robertson, A G.S. | Surgenor, A E. | 3D3 | Atp-binding | Cell cycle | Dna damage | Dna repair | Docking | Drug design | Kinase | Nuclear protein | Nucleotide-binding | Oncology | Phosphorylation | Polymorphism | Serine/threonine-protein kinase | Transferase | Ubl conjugation | Virtual screening
