A pharmacophore docking algorithm and its application to the cross-docking of 18 HIV-NNRTI's in their binding pockets.

The docking of small molecules into the binding site of a target protein is an important but difficult step in structure-based drug design. The performance of a docking algorithm is usually evaluated by re-docking ligands into their native binding sites. We have explored the cross-docking of 18 HIV-NNRTIs (non-nucleoside inhibitors of HIV reverse transcriptase) of which the ligand-protein structure has been determined: each of the 18 ligands was docked into each of the 18 binding sites. The docking algorithms studied are an energy-based simulated annealing algorithm and a novel pharmacophore docking algorithm. It turns out that the energy-based docking of the ligands into non-native pockets is far less successful than the docking into their native pockets. The results can be improved by using explicit pharmacophore information, and by docking a ligand into a panel of protein structures and selecting the ligand-protein-combination with the lowest interaction energy as the final result. (C) 2003 Wiley-Liss, Inc.