Spinach affects the Water

People often ask what a fragment is.  I like to paraphrase Justice Potter and say that it is like pornography; it is in the eye of the beholder.  I am not one for hard and fast rules as to what a fragment should be.  But, I also have a definite opinion what a fragment is NOT.  To me, what a fragment should be is easily described: relatively unadorned molecules.  I have a whole set of rules as to what the substituents should look like (coined the Zartler Optical Filter or ZOF by a cheeky comp chem friend).  In this paper, a group from Merck Serono decide to probe exactly what role the spinach on fragments play.  

Specifically, they deconstructed a TIE2 inhibitor (Figure 1) into its core hinge binding motif (Figure 2). 

Figure 1.  Crystal Structure of the Intact Inhibitor

This hinge binding motif has the advantage in that "decoration" can be introduced at the 4 or 8 position (Figure 2) as well as giving three donor/acceptor moieties. 

Figure 2. 4-Amino-8H-pyrido[2,3-d] pyrimidin-5-one (compound 1)
as core hinge binding motif.

They determined crystal structures for this molecule and four related fragments (Figure 3)

Figure 3.  Fragments for this study.

and then went to town on them with in silico methods to study the roles of water.  In one of those "gotta love it" moments, they classified the waters as "happy" or "unhappy", depending on whether they have positive or negative free energy, respectively.

So, what do we learn?  First, changes in the decoration leads to different binding modes.  In this case, they conclude that replacement of different water molecules leads to differences in binding modes.  Well, not surprising.  But, I think this is part of a trend, studying water and how fragments affect them, and vice versa.  In fact, the authors suggest using WaterMap could help to rationalize the roles of waters.  So, are we entering a brave new world of experimental verification of in silico predictions?