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Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein-ligand crystallography

DOI: 10.1016/j.bmc.2012.09.024 DOI Help
PMID: 23058106 PMID Help

Authors: Cornelis Matijssen (Institute of Cancer Research, Haddow Laboratories, Sutton, Chester Beatty Laboratories, Chelsea, London) , M. Cris Silva-santisteban (Institute of Cancer Research, Haddow Laboratories, Sutton, Chester Beatty Laboratories, Chelsea, London) , Isaac M. Westwood (Institute of Cancer Research, Haddow Laboratories, Sutton, Chester Beatty Laboratories, Chelsea, London) , Samerene Siddique (Institute of Cancer Research, Haddow Laboratories, Sutton) , Vanessa Choi (Institute of Cancer Research, Haddow Laboratories, Sutton, Chester Beatty Laboratories, Chelsea, London) , Peter Sheldrake (Institute of Cancer Research, Haddow Laboratories, Sutton) , Rob L. M. Van Montfort (Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research) , Julian Blagg (Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: September 2012
Diamond Proposal Number(s): 6385

Open Access Open Access

Abstract: Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.

Journal Keywords: Binding; Checkpoint; Crystallography; X-Ray; Humans; Ligands; Molecular; Protein; Tertiary; Protein-Serine-Threonine; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)