Due to their pivotal role in various biological processes and in many diseases, proteins are frequent candidates for drug design studies investigating the interactions between proteins and their binding partners. Being very flexible molecules, proteins can undergo considerable conformational changes upon forming a complex with a ligand. The magnitude of such flexibility can vary from small reorientations of single side chains at the binding site to global loop or whole domain movement. Hence, the appropriate representation of protein flexibility in molecular docking methods is of ample importance for the success of drug design projects. However, due to its computational complexity, the efficient and accurate inclusion of global protein flexibility still marks a major challenge in this field. Here, a newly developed approach that efficiently includes receptor flexibility into grid-based protein-ligand docking is presented. The method combines fast grid-based energy computations with an interpolation scheme allowing for continuous shifting between a set of receptor deformations during docking. This ensemble of structures is used to represent the flexibility of the receptor protein and can be of arbitrary size and source. Several alternatives for the choice of structure input are presented, each containing a variable amount of knowledge on already known bound receptor structures. The method is tested on various pharmaceutically relevant receptor-ligand complexes and yields significantly improved docking results in contrast to the conventional rigid receptor docking. In addition, the flexible receptor docking shows the potential for identifying the deformations within a structure ensemble that show the largest similarity towards the actual bound receptor form. The ability to reproduce near-native ligand binding modes in the great majority of tested cases comes at only small additional computational cost and is thus providing a promising approach to be employed in virtual screening applications.     «

Due to their pivotal role in various biological processes and in many diseases, proteins are frequent candidates for drug design studies investigating the interactions between proteins and their binding partners. Being very flexible molecules, proteins can undergo considerable conformational changes upon forming a complex with a ligand. The magnitude of such flexibility can vary from small reorientations of single side chains at the binding site to global loop or whole domain movement. Hence, th...     »