Treffer: Docking of hydrophobic ligands with interaction-based matching algorithms

Motivation: Matching of chemical interacting groups is a common concept for docking and fragment placement algorithms in computer-aided drug design. These algorithms have been proven to be reliable and fast if at least a certain number of hydrogen bonds or salt bridges occur However, the algorithms typically run into problems if hydrophobic fragments or ligands should be placed. In order to dock hydrophobic fragments without significant loss of computational efficiency, we have extended the interaction model and placement algorithms in our docking tool FlexX. The concept of multi-level interactions is introduced into the algorithms for automatic selection and placement of base fragments. Results: With the multi-level interaction model and the corresponding algorithmic extensions, we were able to improve the overall performance of FlexX significantly. We tested the approach with a set of 200 protein-ligand complexes taken from the Brookhaven Protein Data Bank (PDB). The number oftest cases which can be docked within 1.5 Å RMSD from the crystal structure can be increased from 58 to 64%. The performance gain is paidfor by an increase in computation time from 73 to 91 s on average per protein-ligand complex.