Oliv Eidam and Alex Satz at Roche have published a useful paper that compares a number of the company’s DNA-encoded libraries. There are plenty of papers on these things, but comparisons and general principles are much harder to get ahold of. In this case, they’re showing the results of 16 different libraries (made via different chemistries and building blocks) against two targets, a kinase and a phosphodieserase. The smallest library had about one million compounds in it, most were in the tens of millions, and the largest had (potentially) 100 billion compounds or so (this one was a four-step synthesis scheme).
But one of the lessons that comes out of this work is that library size had no real correlation with hit rate (that whopper library, for example, had no hits at all against these two targets). The others gave compounds that, on resynthesis, were anywhere from 2 nM to double-digit micromolar hits. Of the 57 compounds that were resynthesized (with just a methyl truncating whatever linker they had to the DNA), 35 showed activity at some level. Looking at the structures, several things are clear: for one, none of these structures were to be found in the regular Roche screening deck, CHEMBL, or the patent literature. They were all novel. Their molecular weights varied between 250 and 600, but potency did not correlate at all with increasing MW or with increasing logP (most of the compounds came in between 3 and 4 in cLogP). That’s as opposed to general screening deck, where logP does indeed (and unfortunately) correlate.
And another interesting thing was that a disproportionate number of hits were actually truncates – compounds that did not go through the whole three- or four-step plan for the library, but were intermediates along the way. That would suggest that the more elaborate DNA-encoded schemes, generating larger and more complex chemical matter, may turn out to be a waste of time (or at least waste more of it than they’re worth). It may be too early to draw that conclusion, but it’s something to keep an eye on. . .