Receptor Flexibility in Ligand Docking and Virtual Screening

Abstract

It is now well recognized that receptor flexibility plays an important role in protein-ligand binding. This flexibility can concern not only the mobility and reorganization of side chains in the binding site but also conformational changes of the whole molecule, which makes modeling of ligand docking more challenging. We give here an overview of existing approaches to treating receptor flexibility in protein-ligand docking and virtual screening that range from approximate to more accurate methods, including the use of normal modes in accounting for global conformational changes of the receptor or the use of more precise force fields. In addition, we describe recent successful applications of such approaches that have led to the design or discovery of new lead compounds with therapeutic relevance. These new developments in protein-ligand docking and screening are increasingly applied for better prediction of binding affinities. In view of the ever-increasing power of machine computation, a better accounting of the flexibility of the receptor is justified in order to improve the prediction of ligand binding in the search for new drug candidates by virtual screening.