Peter Oledzki

The proper handling of water in active sites is still a largely unsolved problem in structure-based drug design. We propose a novel strategy that allows for water molecules to be taken into consideration during placement generation in docking. The water can be either placed manually and fixed in orientation or kept rotatable, so that according to the ligand poses, it can best possibly form interactions with the protein and the small molecule. Also, the water can be made permanent or displaceable, so that the ligand placements and scores determine whether the water stays or is removed. This treatment is important for modeling buried or conserved water that is replaced by stronger binding ligands. Finally, aside of the manual placement, FlexX can suggest potential water positions which are then subjected to either of the above ways of handling such water. We present this novel technology together with application examples, illustrating the usefulness of the procedure.