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.
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.
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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.
1 comment:
It's reminiscent of BioSolveIT's ReCore platform. However, some of the examples are pretty simple and could probably be arrived at more easily by "medchemists with pads of paper".
And as mentioned, experimental verification would be nice.
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