Postgraduate Researchers in Science Medicine Conference 2005: Abstracts
Virtual screening of the X-ray crystal structure of human Thymidine Phosphorylase with the NCI and ACD databases
Mehdi Rajabi, Sally Freeman and Richard Bryce
Thymidine phosphorylase (TP) catalyses the reversible conversion of thymidine to thymine and 2-D-α-deoxyribose-1-phosphate. TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF) which is implicated in the growth of solid tumours thus making it a target for anti-cancer chemotherapy. The best TP inhibitors (nanomolar) known are 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]uracil (TPI) and 5-bromo-6-[(2-aminoimidazol)methyl]uracil, however these are associated with poor pharmacokinetic properties. In a recent virtual screening study from this laboratory using a homology model of TP 1-methyl-2,5-dioxo-4-pentyl-4-imidazolidinecarbaldehyde semicarbazone was identified as a non-uracil inhibitor of TP 2. However it was shown to have an IC 50 value of 77 μM with human TP. This low activity, coupled with the recent availability of the X-ray coordinates of human TP 1, prompted further virtual screening efforts.
The X-ray crystal structure of human TP complexed with TPI (resolution 2.1 Å) provides the first structural insight into binding at this active site and forms a basis for designing novel inhibitors with increased potency and specificity. Databases of hydantoin and imidazole based structures were created from the NCI and Available Chemical database (ACD). In silico screening of these databases with the X-ray structure of human TP using DOCK 4.0 has identified novel active site inhibitors of TP. The top NCI compounds have been shown to be μM inhibitors of TP. Best energy scoring compounds identified from the ACD database are currently being synthesised for biological evaluation.
References
1. McNally, V.A.; Gbaj, A.; Douglas, K.T.; Stratford, I.J.; Jaffar, M.; Freeman, S.; Bryce, R.A. Bioorg. Med. Chem. Lett. 2003, 13, 3705.
2. Norman, R.A.; Barry, S.T.; Bate, M.; Breed, J.; Colls, J.G.; Ernill, R.J.; Luke R.W.A.; Minshull, C.A.; McAllister, M.S.B.; McCall, E.J.; McMiken, H.H.J.; Paterson, D.S.; Timms, D.; Tucker, J.A.; Pauptit, R.A. Structure. 2004, 12, 75.
Mehdi Rajabi, University of Manchester, School of Pharmacy and Pharmaceutical Sciences, Manchester, M13 9PL, United Kingdom
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