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. T hese algorithms have been proven to be reliable and fast if at least a cert ain 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 c omputational efficiency we have extended the interaction model and placemen t algorithms in our docking tool FlexX. The concept of multi-level interact ions is introduced into the algorithms for automatic selection and placemen t of base fragments. Results: With the multi-level interaction model and the corresponding algor ithmic extensions, we were able to improve the overall performance of FlexX significantly. We tested the approach with a set of 200 protein-ligand com plexes taken from the Brookhaven Protein Data Bank (PDB). The number of tes t cases which can be docked within 1.5 Angstrom RMSD from the crystal struc ture can be increased from 58 to 64%. The performance gain is paid for by a n increase in computation time from 73 to 91 s on average per protein-ligan d complex.