We developed BSP-SLIM, a new method for ligand–protein blind docking using low-resolution protein structures. For a given sequence, protein structures are first predicted by I-TASSER; putative ligand binding sites are transferred from holo-template structures which are analogous to the I-TASSER models; ligand–protein docking conformations are then constructed by shape and chemical match of ligand with the negative image of binding pockets. BSP-SLIM was tested on 71 ligand–protein complexes from the Astex diverse set where the protein structures were predicted by I-TASSER with an average RMSD 2.92 Å on the binding residues. Using I-TASSER models, the median ligand RMSD of BSP-SLIM docking is 3.99 Å which is 5.94 Å lower than that by AutoDock; the median binding-site error by BSP-SLIM is 1.77 Å which is 6.23 Å lower than that by AutoDock and 3.43 Å lower than that by LIGSITECSC. Compared to the models using crystal protein structures, the median ligand RMSD by BSP-SLIM using I-TASSER models increases by 0.87 Å, while that by AutoDock increases by 8.41 Å; the median binding-site error by BSP-SLIM increase by 0.69Å while that by AutoDock and LIGSITECSC increases by 7.31 Å and 1.41 Å, respectively. As case studies, BSP-SLIM was used in virtual screening for six target proteins, which prioritized actives of 25% and 50% in the top 9.2% and 17% of the library on average, respectively. These results demonstrate the usefulness of the template-based coarse-grained algorithms in the low-resolution ligand–protein docking and drug-screening. An on-line BSP-SLIM server is freely available at http://zhanglab.ccmb.med.umich.edu/BSP-SLIM. Proteins 2012. © 2011 Wiley Periodicals, Inc.