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–proteincombination with the lowest interaction energy as the final result. Proteins 2004;54:000–000. © 2003 Wiley‐Liss, Inc.