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.
Daeyaert
Frits
F
Center for Molecular Design, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica N.V., Antwerpsesteenweg 37, 2350 Vosselaar, Belgium. fdaeyaer@prdbe.jnj.com
de Jonge
Marc
M
Heeres
Jan
J
Koymans
Luc
L
Lewi
Paul
P
Vinkers
Maarten H
MH
Janssen
Paul A J
PA
D000465:Algorithms; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D006678:HIV / Q000187:drug effects / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013816:Thermodynamics; D013997:Time Factors
D019380:Anti-HIV Agents; D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase