29 March 2012

Fragment docking: promiscuous but good enough?

Computational docking of fragments can be difficult, partly because the energetic differences between possible binding modes can be so small that it’s impossible to select the best one. In a recent paper in J. Med. Chem. Andrew Good and colleagues at Genzyme ask whether docking results are nonetheless good enough to act on.

The researchers were interested in the kinase Pim-1; we’ve previously highlighted their success using SPR-discovered fragments to generate nanomolar inhibitors of this target. In the current paper, they use the program Glide to virtually screen 13,888 fragment-sized molecules from their general collection against Pim-1. About 3% (462) of these were tested in a functional assay at 125 micromolar concentration, resulting in 46 fragments with IC50 better than 100 micromolar. Five diverse representatives of these fragments were then soaked into crystals of Pim-1, and their structures were compared with those from docking.

Overall, only two of the fragments showed a good correlation between the in silico and crystallographic models (rmsd 1.0 Å or better). However, two of the “failures” do make key hydrogen-bond interactions seen in the crystal structures, though some of the hydrophobic interactions are quite different.

As the researchers note:
Fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization.
This seems reasonable, and is consistent with the notion that polar interactions are more directional – and thus perhaps easier to correctly dock – than more generic hydrophobic interactions.

But there may also be something more fundamental going on: the assumption seems to be that the observed crystallographic structures are definitive, but is this an oversimplification? After all, a crystallographically-derived model seldom provides more than one binding mode (though a notable exception led to the first approved fragment-based drug). Perhaps the reason it’s so difficult to score docked fragments is that fragments really can assume multiple binding modes, and our insistence on one single best model is the problem. If this is true, docking models are telling us more about reality than we are giving them credit for. NMR-based models are often presented as an ensemble of structures; perhaps the same should be done for docking? At any rate, NMR studies on Pim-1 with these fragments could prove interesting.


Anonymous said...
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Dr. Teddy Z said...

Dan, I think it is not necessarily that the docking forces a single binding mode, but that Xray only has one binding mode. Proteins are dynamic; NMR structures reports the ensemble of structures. In the past, I have worked on a project where all 40 ensemble NMR structures were used in the docking, it captured some interesting modes for binding.

Dan Erlanson said...

Thanks Teddy,

I completely agree, but sometimes modelers present only their best pose rather than an ensemble of best poses, particularly in publications. It might make sense for computational chemists to treat their models more like those that come out of NMR than those that come out of X-ray.

I do think it would be fun to throw NMR, X-ray, and modeling at a single target and see whether NMR and modeling are able to capture more of the dynamics than X-ray, and Pim-1 seems like it might be a good candidate, though I suppose it is getting a bit large for NMR.