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

• Published in: Bioorganic & medicinal chemistry 2012-11, Vol.20 (22), p.6630-6639
• Main Authors: Matijssen, Cornelis, Silva-Santisteban, M. Cris, Westwood, Isaac M., Siddique, Samerene, Choi, Vanessa, Sheldrake, Peter, van Montfort, Rob L.M., Blagg, Julian
• Format: Article
• Language: English
• Subjects: adenosine triphosphate; benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Binding Sites; Biological and medical sciences; Checkpoint Kinase 2; CHK2; crystal proteins; crystal structure; Crystallography; Crystallography, X-Ray; Flexible docking; Humans; Inhibitor; Kinase; Ligands; Medical sciences; Molecular Docking Simulation; Pharmacology. Drug treatments; Protein Binding; protein kinases; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein Structure, Tertiary; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.09.024

Unconstrained rigid docking, flexible side chain docking and protein crystal structure determinations reveal a water-mediated hinge binding mode for a series of benzimidazole ligands of the protein kinase CHK2. This binding mode is different from those previously postulated in the literature and may provide a useful approach to selective small molecule inhibitor design. 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.