title: Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase.
abstract: Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A 'clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 A away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Birch
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hartshorn
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Tickle
authors.forename: Marcel L
authors.initials: ML
authors.lastname: Verdonk
mesh_terms: D000465:Algorithms; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D009980:Influenza A virus / Q000201:enzymology*; D009981:Influenza B virus / Q000201:enzymology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D014867:Water; D009439:Neuraminidase