H. Claußen

The enzyme aldose reductase (AR) is believed to play an important role in the development of severe degenerative complications of diabetes mellitus. Therefore AR is a potential target for drug design. Since AR has a highly flexible active site it can bind to very different ligands. Although side-chain or even backbone adjustments upon ligand binding are also frequently observed in other proteins, only very few discrete molecular docking approaches take this protein flexibility at least to some extent into account. Full protein flexibility can currently only be handled by time-consuming simulation approaches. We present the new software tool FlexE that addresses the problem of protein flexibility during docking calculations. FlexE can dock flexible ligands into flexible proteins that are represented by an ensemble of structures. On average FlexE takes about five and a half minutes for placing one ligand on a common day workstation. On our target system aldose reductase FlexE is able to reproduce the correct binding modes of different ligands that cause major conformational changes within the active site of the enzyme upon binding.