BSP-SLIM: A blind low-resolution ligand-protein docking approach using predicted protein structures

We developed BSP-SLIM, a new method for ligandprotein 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; ligandprotein 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 ligandprotein complexes from the Astex diverse set where the protein structures were predicted by I-TASSER with an average RMSD 2.92 angstrom on the binding residues. Using I-TASSER models, the median ligand RMSD of BSP-SLIM docking is 3.99 angstrom which is 5.94 angstrom lower than that by AutoDock; the median binding-site error by BSP-SLIM is 1.77 angstrom which is 6.23 angstrom lower than that by AutoDock and 3.43 angstrom 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 angstrom, while that by AutoDock increases by 8.41 angstrom; the median binding-site error by BSP-SLIM increase by 0.69 angstrom while that by AutoDock and LIGSITECSC increases by 7.31 angstrom and 1.41 angstrom, 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 ligandprotein docking and drug-screening. An on-line BSP-SLIM server is freely available at . Proteins 2012. (C) 2011 Wiley Periodicals, Inc.