Abstract 2904: Docking-based virtual screening of Chk1 inhibitors

Abstract

Abstract Checkpoint 1 (Chk1), which is required for checkpoint arrest, is activated in response to DNA damage through the ATM/ATR pathway, and plays an essential role in the regulation of the G2/M checkpoint. Inhibition of Chk1 should abrogate this checkpoint in a manner relevant to the treatment of cancer, and may also induce apoptosis. Selective Chk1 inhibitors should also prove useful to study the regulation of the G2/M checkpoint. Several Chk1 inhibitors are already known, including natural products. UCN-01, a Chk1 inhibitor and staurosporine derivative, is undergoing clinical trials as an anticancer agent. A limited number of additional Chk1 inhibitors have been reported; however, a need to identify more drug-like Chk1 inhibitors is clear. This should be facilitated by the structural information available for the Chk1 kinase domain. The first crystal structure of the kinase domain of human Chk1 has been reported at 1.7Å resolution in 2000. After that, 46 co-crystal structures of Chk1 and inhibitors have also been solved. This puts docking-based virtual screening of Chk1 inhibitors on firm footing. Molecular docking is a very popular method employed to investigate molecular associations and is particularly useful in the drug discovery arena to study the binding of small molecules (ligands) to macromolecules (receptors). To deal with the binding event in a realistic manner, we took into account the conformational flexibility of the ligand and the flexibility of the receptor. In this work, a large collection of crystallographic structures of Chk1 was employed to determine if multiple-structure docking performs better than single-structure docking. Known ligands were used to test the success of docking in binding mode prediction and virtual screening enrichment factors. A chemical library with more than 60,000 compounds was docked into the selected Chk1 structures, and the top-ranked compounds were then tested in experiments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2011-2904