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J Chem Inf Model. 2008 Nov;48(11):2214-25. doi: 10.1021/ci8002254.

Protein-ligand docking against non-native protein conformers.

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Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.


In the validation of protein-ligand docking protocols, performance is mostly measured against native protein conformers, i.e. each ligand is docked into the protein conformation from the structure that contained that ligand. In real-life applications, however, ligands are docked against non-native conformations of the protein, i.e. the apo structure or a structure of a different protein-ligand complex. Here, we have constructed an extensive test set for assessing docking performance against non-native protein conformations. This new test set is built on the Astex Diverse Set (which we recently constructed for assessing native docking performance) and contains 1112 non-native structures for 65 drug targets. Using the protein-ligand docking program GOLD, the Astex Diverse Set and the new Astex Non-native Set, we established that, whereas docking performance (top-ranked solution within 2 A rmsd of the experimental binding mode) is approximately 80% for native docking, this drops to 61% for non-native docking. A similar drop-off is observed for sampling performance (any solution within 2 A): 91% for native docking vs 72% for non-native docking. No significant differences were observed between docking performance against apo and nonapo structures. We found that, whereas small variations in protein conformation are generally tolerated by our rigid docking protocol, larger protein movements result in a catastrophic drop-off in performance. Some docking performance and nearly all sampling performance can be recovered by considering dockings produced against a small number of non-native structures simultaneously. Docking against non-native structures of complexes containing ligands that are similar to the docked ligand also significantly improves both docking performance and sampling performance.

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