FlexX‐Scan: Fast, structure‐based virtual screening

We present a new software module, FlexX-Scan, for high-throughput, structure-based virtual screening. FlexX-Scan was developed with the aim to further speed up the virtual screening process. Based on the incremental construction docking tool FlexX (Rarey et al., J Mol Biol 1996;261:470-489), a compact descriptor for representing favorable protein interaction spots within the protein binding site has been developed. The descriptor is calculated using special-purpose clustering techniques applied to the usual interaction points created by FlexX. The algorithm automatically detects a small set of interaction spots in the binding site for positioning ligand functional groups. The parametrizations of the base placement and incremental construction algorithms have been adapted to the new interaction model. We tested the software tool on a diverse set of 200 protein-ligand complexes from the protein database (PDB) (Kramer et al., Proteins 1999;37:228-241). On average, the algorithm proposes about 90 interaction spots per binding site compared to about 1000 interaction dots in FlexX. We observe that the docking solutions of FlexX-Scan have a root-mean-square deviation from the crystal structure similar to the deviation of docking solutions of standard FlexX. For further validation we also performed virtual screening experiments for cyclin-dependent kinase 2, thrombin, angiotensin-converting enzyme, and dihydrofolat reductase. In these experiments, we screened a set of 34,000 random compounds and a number of known actives for each target. With FlexX-Scan, we achieved comparable enrichments to standard FlexX, with an averaged computing time of 5-10 s per compound, depending on parametrization.