1. Peptidomimetic Design

CCS successfully selected a series of biologically validated small molecule peptidomimetic compounds from commercially available sets of compounds available for purchase. Three dimensional modeling techniques were used on the known active peptide fragment in conjunction with simple bioinformatics analysis to achieve this end. The client company purchased around 60 small molecules based on the modeling, and 12 of these were active against the biological target. This was an unexpected but very pleasing success!

2. Targeted Molecular Dynamics

In collaboration with Biotica, CCS investigated the energetics of geldanamycin and macbecin in the active site of HSP90 using targeted molecular dynamics1,2 in an attempt to rationalise the higher binding affinity of macbecin for the target compared with geldanamycin. The targeted molecular dynamics simulations showed that the energy barrier to achieve the bound conformation of the ligand from the free solution form was greater for macbecin than for geldanamycin. Inspection of x-ray data also revealed differences in hydrogen-bonding which could contribute to the higher affinity observed for macbecin.

1. Ming-Qiang Zhang, Sabine Gaisser, Mohammad Nur-E-Alam, Lesley S. Sheehan, William A. Vousden, Nikolaos Gaitatzis, Gerrard Peck, Nigel J. Coates, Steven J. Moss, Markus Radzom, Teresa A. Foster, Rose M. Sheridan, Matthew A. Gregory, S. Mark Roe, Chrisostomos Prodromou, Laurence Pearl, Susan M. Boyd, Barrie Wilkinson, and Christine J. Martin, J. Med. Chem., vol 51, 5494-5497, 2008

2. Christine J. Martin, Sabine Gaisser,, Iain R. Challis, Isabelle Carletti, Barrie Wilkinson, Matthew Gregory, Chrisostomos Prodromou, S. Mark Roe, Laurence H. Pearl, Susan M. Boyd and Ming-Qiang Zhang, J. Med. Chem., vol 51, 2853-2857, 2008