Pharmacophore modelling on the apoptosis regulating target XIAP-Bir3

XIAP (X-linked inhibitor of apoptosis protein) has been identified to be an endogenous protein that regulates the activity of both initiator (caspase-9) and effector caspases (caspase-3 and-7) and has therefore emerged as promising therapeutic target in cancer therapy [1].

The aim of our study was to generate a reliable pharmacophore model for small drug-like molecules binding at the Bir3 domain of XIAP at the same groove where endogenous Smac (second mitochondria-derived activator of caspases) and caspase-9 are binding. A GRID based pharmacophore model was recently published by Ortuso et. al. [2]. Since this model showed only poor selectivity it was further optimized using the ligand target interactions of the natural ligand Smac and its analogue (PDB entries 1G3F, 1TFQ, resp.; [3]). The refined model was validated by means of a small database containing 30 compounds with known inhibitory effects on the Bir3 domain; 29 out of 30 structures could be found by our hypothesis. Subsequently a virtual screening filtering experiment of commercial databases was performed revealing hit rates from 0.17 to 2.07% depending on the used libraries. Fit values and docking experiments aided in the final selection of promising test candidates which were successfully evaluated for their ability to enhance apoptosis of Jurkat and XIAP overexpressing Jurkat cells affording the proof of concept. Evidence is given that natural products can be found by the pharmacophore model because embelin, a known natural product inhibitor of XIAP [4], could be retrieved from commercial databases. Our intention is to apply this validated in silico tool for the virtual screening of our in house natural product database. Thus, we hope to identify new lead structures from natural sources in a target-oriented way able to interact with XIAP in the apoptotic pathway.

References: 1. Liston, P. et al. (2003), Oncogene 22: 8568–8580. 2. Ortuso, F. et al. (2006), Bioinformatics, doi: 10.1093/bioinformatics/ btl115. 3. Berman, H. et al. (2000), Nucleic Acids Res. 28: 235–242. 4. Nikolovska-Coleska, Z. et al. (2004), J. Med. Chem. 47: 2430–2440.