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Fragment Screening

Fragment screening is a powerful tool for ligand discovery that is often complementary to traditional high-throughput screening. The most common fragment screening methods employ NMR [1] or x-ray crystallography [2] and screen compounds of lower molecular weight (fragments) than is typical with HTS. The binding energies involved are correspondingly weaker but this fact is mitigated by the higher information content (binding location and mode) provided by these methods. Fragment screening is therefore ideally suited for structure-based approaches to drug discovery. Recently, a novel screening method employing disulfide fragment trapping was described [3]. This method allows the targeting of specific sites on a protein by utilizing native or introduced cysteine residues. UCSF has entered into a research and license agreement with Sunesis Pharmaceuticals that enables the SMDC to utilize this technology for academic purposes. The SMDC compound collection includes fragment libraries optimized for either x-ray or disulfide trapping methods.

[1] Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science, 1996, 274, 1531-1534.

[2] Nienaber, V. L.; Richardson, P. L.; Klinghofer, V.; Bouska, J. J.; Giranda, V. L.; Greer, J. Nat. Biotechnol. 2000, 18, 1105-1108.

[3] Erlanson, D. A.; Wells, J. A.; Braisted, A. C. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 199-223.

For more information about the SMDC Fragment Screening, please see Disulfide Trapping and Performing Screens.