Dynamic combinatorial chemistry (DCC)-based approach to drug discovery

To aid the drug discovery effort by the epigenetics community, we are interested in developing novel methods of lead identification. In the disulfide-based dynamic combinatorial mass spectrometric (DCMS) technique, a ‘support-ligand’ that binds to the active site and which contains a thiol side chain is allowed to react reversibly (either at the active site or in solution) with a set of thiols to form a mixture of disulfides. We then use non-denaturing electrospray ionisation mass spectrometry (ESI-MS) to analyse the protein-disulfide complexes and to identify those disulfides which bind preferentially to the enzyme. We have employed this technique to the rapid identification of nucleic acid demethylases [1] and JmjC histone demethylases. [2]

 

estherwoon-dcc-fig1

estherwoon-dcc-fig2

Selected publications

  1. Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; Yeoh, K. K.; Tian, Y-M.; Claridge, T. D. W.; Rgatcliffe, P. J.; Woon, E. C. Y.;* Schofield, C. J.* Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors. Angew. Chem. Int. Ed. 2012, 51, 6672-6675.
  2. Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L.; Aik, W. S.; Krylova, S. M.; Ma, J. H. Y.; Chan, M. C.; Walport, L. J.; Wegman, D. W.; Dack, K. N.; McDonough, M. A.; Krylov, S. N.; Schofield, C. J. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate dependent nucleic acid demethylase. J. Med. Chem., 2012, 55, 2173-2184.
  3. Rose, N. R.; Woon, E. C. Y.; Kingham, G. L.; King, O. N. F.; Mecinovic, J.; Clifton, I. J.; Ng, S. S.; Talib-Hardy, J.; Oppermann, U.; McDonough, M. A.; Schofield, C. J. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. J. Med. Chem., 2010, 53, 1810-1818.