How to Efficiently Include Receptor Flexibility During Computational Docking

Target-based drug design uses available 3D structural information of receptor molecules to either dock putative ligand molecules to receptor binding sites or to de-novo design new ligands. In many cases accurate prediction of putative binding geometries requires the appropriate inclusion of conformational flexibility of both the ligand as well as the receptor structure. The problem of appropriate treatment of conformational flexibility during docking is also tightly connected to the improvement of scoring a docked ligand-receptor complex. Highly accurate scoring of a ligand placement is only possible if the complex geometry has been predicted with high precision. Considerable progress has already been achieved in modeling the conformational flexibility of small organic ligands during docking. Although of similar importance, receptor flexibility has not been tackled satisfactorily despite the steady increase in computational power. Especially during virtual screening of large drug-like compound libraries the target structure often is still kept rigid. However, many protein structures undergo local structural changes (side chain or loop motions) as well as global changes in the backbone geometry upon complex formation. In recent years, several promising approaches to efficiently tackle receptor flexibility have been introduced ranging from conformational ensemble methods to explicit inclusion of the most relevant receptor degrees of freedom. Possible applications and future directions on improving flexible docking approaches will be discussed.