Fragment based drug discovery

LIGAND-PROTEIN rv. CREATION AND ANALYSIS VII. OTHER BIOPHYSICAL AND 

STATUS OF LATE 1990s create secondary libraries Vm. METHODS FOR FRAGMENT 

Everything should be made as simple as possible, but not simpler 

Traditionally, complete structure elucidation of a new organic compound, either synthesized or namrally occurring, is assisted by a combination of elemental analysis, H NMR, C NMR, and MS techniques [26]. To explain this concept, let us take the example of two molecules 1 and 2 synthesized in om laboratory whose experimentally determined spectra are available [27] Fig. 7.2. 

7 Predictive Methods for Organic Spectral Data Simulation 

7 Predictive Methods for Organie Spectral Data Simulation 

Mass spectrum of 1 showed molecular ion peak (m/z) at 234, along with other fragmentation peaks at 206, 191, 175,165, 121, 107, and 91 (Fig. 7.8). 

The mass spectrum of the compound 2 showed molecular ion peak at 258 and base peak at 174. 

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Zartier ER, Shapiro MJ. Fragonomics fragment-based drug discovery. Curr Opin Chem Biol 2005 9 366-70. 

Klages, J., Coles, M., Kessler, H. NMR-based screening a powerful tool in fragment-based drug discovery. Mol. Biosyst. 2006, 2, 319-331. 

Keywords NMR, drug discovery, fragment based drug discovery, SAR by NMR, SAR by ILOEs, hit to lead... 

Tethering Fragment-based Drug Discovery by Mass Spectrometry... 

One of the biggest challenges in fragment-based drug discovery is not finding fragments but linking them. In the case of TS (above), we used structure-based... 

Erlanson, D.A., Wells, J.A., Braisted, A.C. Tethering fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 199-223. 

Tethering is a registered service mark of Sunesis Pharmaceuticals, Inc., for its fragment-based drug discovery. 

Researchers at Sunesis pharmaceuticals have developed a fragment-based drug discovery method termed tethering [25]. The approach, which is illustrated in Scheme 2.6, shares a number of features with DCC. Whereas protein-directed DCLs equilibrate small molecules via disulfide formation, say, in the presence of a protein that acts as a thermodynamic trap, tethering uses a cysteine residue on the protein surface to reversibly capture small-molecule thiol fragments from solution. Tethering is designed... 

Poulsen, S.-A. Bomaghi, L. F. Fragment-based drug discovery of carbonic anhydrase 11 inhibitors by dynamic combinatorial chemistry utilizing alkene cross metathesis. Bioorg. Med. Chem. 2006,14, 3275-3284. 

FBDD reviews (a) Congreve, M. Chessari, G. Tisi, D. Woodhead, A. J. Recent developments in fragment-based drug discovery. J. Med. Chem. 2008, 51, 3661-3680. (b) Erlanson, D. A. Fragment-based lead discovery A chemical update. Curr. Opin. Biotechnol. 2006,17, 643-652. 

Poulsen, S.-A. Kruppa, G. Ft. In situ fragment-based medicinal chemistry Screening by mass spectrometry, hi Fragment-based drug discovery Practical aspects, Zartler, E. R., Shapiro, M. J. editors. Wiley, London, Chapter 7,2008. 

Erlanson DA, McDowell RS, O Brien T. Fragment-based drug discovery. / Med Chem 2004 47 3463-82. 

Congreve, M., Chessari, C., Tisi, D., Woodhead, A. (2008) Recent advances in fragment-based drug discovery. J Med Chem 51, 3661-3680. 

Brewer, M., Ichihara, O., Kirchhoff, C., Schade, M., Whittaker, M. (2008) Assembling a fragment library. Fragment-Based Drug Discovery A Practical Approach, in (Zartler, E., Shapiro, M. J. eds.), pp. 39-62. 

Hesterkamp, T., Barker, J., Davenport, A., Whittaker, M. (2007) Fragment based drug discovery using fluorescence correlation spectroscopy techniques challenges and solutions. Curr Top Med Chem 7, 1582-1591. 

Fragment-Based Drug Discovery A Practical Approach Edited by Edward R. Zartler and Michael J. Shapiro 2008 John Wiley Sons, Ltd. ISBN 978-0-470-05813-8... 

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