Many available methods aimed at incorporating the receptor flexibility in ligand docking are computationally expensive, require a high level of user intervention, and were tested only on benchmarks of limited size and diversity. Here we describe the four-dimensional (4D) docking approach that allows seamless incorporation of receptor conformational ensembles in a single docking simulation and reduces the sampling time while preserving the accuracy of traditional ensemble docking. The approach was tested on a benchmark of 99 therapeutically relevant proteins and 300 diverse ligands (half of them experimental or marketed drugs). The conformational variability of the binding pockets was represented by the available crystallographic data, with the total of 1113 receptor structures. The 4D docking method reproduced the correct ligand binding geometry in 77.3% of the benchmark cases, matching the success rate of the traditional approach but employed on average only one-fourth of the time during the ligand sampling phase.