Placement of medium-sized molecular fragments into active sites of proteins

Summary We present an algorithm for placing molecular fragments into the active site of a receptor. A molecular fragment is defined as a connected part of a molecule containing only complete ring systems. The algorithm is part of a docking tool, called FlexX, which is currently under development at GMD. The overall goal is to provide means of automatically computing low-energy conformations of the ligand within the active site, with an accuracy approaching the limitations of experimental methods for resolving molecular structures and within a run time that allows for docking large sets of ligands. The methods by which we plan to achieve this goal are the explicit exploitation of molecular flexibility of the ligand and the incorporation of physicochemical properties of the molecules. The algorithm for fragment placement, which is the topic of this paper, is based on pattern recognition techniques and is able to predict a small set of possible positions of a molecular fragment with low flexibility within seconds on a workstation. In most cases, a placement with rms deviation below 1.0 Å with respect to the X-ray structure is found among the 10 highest ranking solutions, assuming that the receptor is given in the bound conformation.