2C3K
Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification
Summary for 2C3K
| Entry DOI | 10.2210/pdb2c3k/pdb |
| Related | 1IA8 1NVQ 1NVR 1NVS 2BR1 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO 2C3J 2C3L |
| Descriptor | SERINE/THREONINE-PROTEIN KINASE CHK1, 4-[3-(1H-BENZIMIDAZOL-2-YL)-1H-INDAZOL-6-YL]-2-METHOXYPHENOL (3 entities in total) |
| Functional Keywords | drug design, molecular modeling, molecular recognition, oncology, atp-binding, cell cycle, dna damage, dna repair, kinase, nuclear protein, nucleotide-binding, phosphorylation, polymorphism, serine/threonine-protein kinase, transferase, ubl conjugation |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 34504.53 |
| Authors | Foloppe, N.,Fisher, L.M.,Francis, G.,Howes, R.,Kierstan, P.,Potter, A. (deposition date: 2005-10-10, release date: 2005-11-23, Last modification date: 2023-12-13) |
| Primary citation | 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 Cited by 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: 16289938DOI: 10.1016/J.BMC.2005.10.022 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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