Ensemble Docking in Drug Discovery

Abstract

Ensemble docking corresponds to the generation of an "ensemble" of drug target conformations in computational structure-based drug discovery, often obtained by using molecular dynamics simulation, that is used in docking candidate ligands. This approach is now well established in the field of early-stage drug discovery. This review gives a historical account of the development of ensemble docking and discusses some pertinent methodological advances in conformational sampling.

Figure 1

Schematic workflow of ensemble docking using the M₂ muscarinic G-protein-coupled receptor as a model receptor: computer simulations using MD are performed to construct structural ensembles of different receptor conformations that can account for the receptor flexibility. Meanwhile, a compound library can be prepared from chemical databases, e.g., ZINC, ChemBridge, National Cancer Institute (NCI) Diversity Set, Natural Product Library, etc. Finally, molecular docking to the receptor ensembles (i.e., ensemble docking) are carried out to identify top-ranked compounds for experimental testing. To see this figure in color, go online.