Molecular docking methods are extensively used to predict the interaction between protein-ligand systems in terms of structure and binding affinity, through the optimization of a physics-based scoring function. However, the computational requirements of these simulations grow exponentially with: (1) the global optimization procedure, (2) the number and degrees of freedom of molecular conformations generated, and (3) the mathematical complexity of the scoring function.In this work we introduce a novel molecular docking method named METADOCK 2, which incorporates several novel features such as (1) a ligand-dependent blind docking approach that exhaustively scans the whole protein surface to detect novel allosteric sites, (2) an optimization method to enable the use of a wide branch of metaheuristics, and (3) a heterogeneous implementation based on multicore CPUs and multiple Graphics Processing Units (GPUs). Two representative scoring functions implemented in METADOCK 2 are extensively evaluated in terms of computational performance and accuracy using several benchmarks (such as the well-known DUD) against AutoDock 4.2 and AutoDock Vina.Results place METADOCK 2 as an efficient and accurate docking methodology able to deal with complex systems where computational demands are staggering and which outperforms both AutoDock Vina and AutoDock 4.https://Baldoimbernon@bitbucket.org/Baldoimbernon/metadock_2.git.Supplementary data are available at Bioinformatics online.