2c3l
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IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION
OverviewOverview
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 ... [(full description)]
About this StructureAbout this Structure
2C3L is a [Single protein] structure of sequence from [Homo sapiens] with SO4 and IDZ as [ligands]. Active as [[1]], with EC number [2.7.1.37]. Full crystallographic information is available from [OCA].
ReferenceReference
Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification., Foloppe N, Fisher LM, Francis G, Howes R, Kierstan P, Potter A, Bioorg Med Chem. 2006 Mar 15;14(6):1792-804. Epub 2005 Nov 9. PMID:16289938
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- Homo sapiens
- Single protein
- Fisher, L.M.
- Foloppe, N.
- Francis, G.
- Howes, R.
- Kierstan, P.
- Potter, A.
- IDZ
- SO4
- Atp-binding
- Cell cycle
- Dna damage
- Dna repair
- Drug design
- Kinase
- Molecular modeling
- Molecular recognition
- Nuclear protein
- Nucleotide-binding
- Oncology
- Phosphorylation
- Polymorphism
- Serine/threonine-protein kinase
- Transferase
- Ubl conjugation