Protein structure prediction provides comparable performance to crystallographic structures in docking-based virtual screening

Structure based virtual screening has largely been limited to protein targets for which either an experimental structure is available or a strongly homologous template exists so that a high-resolution model can be constructed. The performance of state of the art protein structure predictions in virtual screening in systems where only weakly homologous templates are available is largely untested. Using the challenging DUD database of structural decoys, we show here that even using templates with only weak sequence homology (<30% sequence identity) structural models can be constructed by I-TASSER which achieve comparable enrichment rates to using the experimental bound crystal structure in the majority of the cases studied. For 65% of the targets, the I-TASSER models, which are constructed essentially in the apo conformations, reached 70% of the virtual screening performance of using the holo-crystal structures. A correlation was observed between the success of I-TASSER in modeling the global fold and local structures in the binding pockets of the proteins versus the relative success in virtual screening. The virtual screening performance can be further improved by the recognition of chemical features of the ligand compounds. These results suggest that the combination of structure-based docking and advanced protein structure modeling methods should be a valuable approach to the large-scale drug screening and discovery studies, especially for the proteins lacking crystallographic structures. (C) 2014 Elsevier Inc. All rights reserved.