Validations

Studies have been conducted on two targets to demonstrate the performance of the DrugFinder screening system. The targets were selected to represent significant differences in both the docking site shape and ligand functionality.

The first target is the kinase cyclin dependent kinase 2 (CDK2). Cyclin dependent kinases are a family of 16 serine/threonine kinases that are important regulators of the mammalian cell cycle [1], [2]. CDK2 activity has been linked to many human cancers and thus it has been extensively studied, resulting in over 135 crystal-structures [1] being submitted to the protein databank [3]. The CDK2 binding site is deep and rather hydrophobic in character. The PDB structure denoted by the code 2R3J was selected as the query protein and ligand.
The second target, Thrombin [4], was selected due to its applicability as a cardiovascular target and the different challenges it poses as docking target. The thrombin active site is not as deep as the CDK2 site, showing the extended configuration typical of many proteinases. Also, in contrast to CDK2, the site is quite polar, with many potential hydrogen bonds and a key selectivity pocket that accommodates charged residues. The PDB structure denoted by the code 1O3D was selected as the query protein and ligand.

References

[1] H. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. Bhat, H. Weissig, I. Shindyalov, and P. Bourne. The protein data bank. Nucl. Acid. Res., 28:235–242, 2000.

[2] Thierry O. Fischmann, Alan Hruza, José S. Duca, Lata Ramanathan, Todd Mayhood, William T. Windsor, Hung V. Le, Timothy J. Guzi, Michael P. Dwyer, Kamil Paruch, Ronald J. Doll, Emma Lees, David Parry, Wolfgang Seghezzi, and Vincent Madison. Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers, 89(5):372–379, 2008.

[3] Chou S.H., Zhu L., and Reid B.R.

[4] Kwon T.K. and Nordin A.A. Identification of cdk2 binding sites on the p27kip1 cyclin-dependent kinase inhibitor. Oncogene, Feb 1998.