A Great New Tool....for what?

As has been noted here, frequently, is that in silico design of fragments is very hard, fraught with problems, and often leads to crap.  As was pointed out elsewhere recently, computational tools are getting more powerful, but still don't have chemical intuition leading to suspect structures.  I am assuming that computational scientists have heard the critiques because we are seeing better and better work, with more experimental verification.  Now, what about better structures?  In this paper from Kaken Pharmaceutical and Toyohashi University of Technology, the propose a way to do this.  

In silico tools can be divided into two classes, structure-based and ligand-based design (TOPAS and Flux are two examples of the latter).  These methods are based upon biological evolution: reproduction, mutation, cross-over, and selection.  Mutation and cross-over are vital for creating new chemical structures.  Mutation can be atom or fragment-based.  In a previous study by these authors, the atom-based method was used for the mutation, in which an atom is modified into another atom to explore the chemical space. The method often resulted in a lot of unfavorable structures that contained invalid hetero−hetero

atom bonds such as O−O and N−F. The fragment mutation approach avoids this problem, especially when the fragments are from known molecules (this assumes they were synthesized and thus could be again). This is one key to their approach: chemical feasibility is considered.

Figure 1.

The method (Figure 1) uses a known molecule to "navigate a chemical space to be explored." [I love this phrase, but immediately I think of this.]  The reference molecule is also used to generate the seed fragments (Figure 2), which can be rings, linkers, or side chains.  

Figure 2

 With a good set of seeds, connection rules, and so forth, the key is the mutation and cross-over events.  A parent molecule is randomly selected and then one of three operations occurs: 1. add a fragment, 2. remove a fragment, or 3. change a fragment.  For "Add Fragment", if the base fragment is ring, then a new linker, side chain, or ring is chosen.  If the base fragment is linker or side chain, then a ring is added. "Remove fragment" removes a terminal fragment.  "Replace fragment" is a fragment for fragment swap (Figure 3). The cross-over function is also shown in Figure 3. 

Figure 3

Then they used this protocol to design ligands against GPCR (AA2A and 5HT1A). 

Figure 4.

Figure 4 shows some of the results against AA2A.  They were able to generate a molecule that is very similar to a known active and because of the generation of the fragments these are all presume to be chemically feasible.  

 

So, my first complaint here is where's the experimental verification?  OK, this is not a medchem journal, but still...  I am not nearly as savvy as some of our regular readers, but I am completely missing the forest for the trees here.  This paper first struck me as pretty neat, but then the "neat-o" factor fell away and I was left asking "what is it for?"  To me, this would seem to be a patent-busting tool.  We need to generate a structure that is very similar to billion dollar compound A, but it cannot contain fragments X, Y, and Z.  Is this better than locking your favorite medchemists in a room with a few pads of paper?  I am not being flippant here.  If I am missing something, please let me know in the comments.