29 August 2011

Fragment docking: it’s all about ligand efficiency

A widespread belief holds that it is more difficult to computationally dock fragment-sized molecules than lead-sized or drug-sized molecules. But is this really true? And if so, why? These questions are tackled by Marcel Verdonk and colleagues at Astex in a recent paper in J. Med. Chem.

The researchers examined 11 targets for which they had multiple crystal structures of each with bound fragments (which contained up to 15 non-hydrogen atoms) and larger molecules (which contained at least 20 non-hydrogen atoms); these crystal structures were the “correct” structures against which computational models could be judged. A total of 106 fragments and 100 larger molecules were then docked against their target proteins using a variety of different methods.

Surprisingly, the overall results were not overly impressive (<70% correct depending on methodology – often much less). But even more surprisingly, there was no difference between the success rates of the fragments and that of the larger molecules. However, the reasons for the poor performance were different. In the case of fragments, the problem was often that the scoring function didn’t recognize the correct solution; the energetics were just too subtle. In the case of the larger molecules, though, the problem was more often one of sampling: the docking program failed to produce the conformation of protein or ligand that corresponded to the correct solution, so it had no opportunity to score it. Potency made no difference: high-affinity compounds fared just as poorly as lower affinity compounds. What did make a difference, though, was ligand efficiency: compounds with high ligand-efficiency (> 0.4 kcal/mol/atom) were docked with considerably greater success than those with lower ligand efficiencies. As the authors point out, this makes sense intuitively:
High LE compounds form high-quality interactions with the target, which should make it easier for a docking program (both from a scoring and search perspective) to dock these compounds correctly.
So the next time you see a computational model of a protein-ligand complex, you might want to take a closer look at ligand efficiency to get a sense of how trustworthy the structure might be.


Vladimir Chupakhin said...

70% is really good prediction quality for fragments by the way. And for me it's seems rather strange....
...checked the article: performance is 59% for fragments - not 70%, and also several tweaks were used
1. Diverse solutions
2. Further minimization of the structure.
These two will enlarge computational time drastically!!!
So, in my opinion is better to say "we hardly can predict the binding pose of the fragment using default parameters with even 50% accuracy (< 2.0A RMSD)"

Dan Erlanson said...

Thanks - I did try to emphasize that the results were less than 70%. In Table 3 the fragment set had scores as high as 69.5%, albeit using native docking and an AMBER force field. But your broader point about the difficulty of making accurate predictions is correct, as is the authors' that ligand efficiency does make a meaningful difference.