[cing]

I agree with the sentiment of this paper (AF can enable drug discovery), but in this specific instance, the authors had a real opportunity contribute a general finding to the scientific community but instead they put in the lowest amount of effort (to a point where they're almost saying nothing at all).

The target had dozens of related structures in the protein databank, including relatives with ~40% sequence identity. This target family has a very similar structure, and conserved active site residues. It's relevant that this target has approved cross-CDK family inhibitors (and thousands of data points of CDK family binders on ChEMBL). The conventional way to enable structure-based design is to build a homology model using a similar structure (see here: https://swissmodel.expasy.org/repository/uniprot/Q8IZL9?temp...), and in this case, there is very low deviation from the AF2 model and this "old fashioned" approach.

To recap, this target had a decent model that would have likely sufficed for drug discovery. The community already knows that "homology models" can be used for structure-based drug design, so any methodological hypotheses of this paper are not supported by evidence.

[dekhn]

Although I agree the authors could have done homology modelling, in this case AlphaFold is already doing that. It knows all the related sequences (through the sequence database similarity graph that it embeds) and has a very sophisticated modelling system. In my guess (I'd have to check with my old friends to be sure) it does as well as if not better in producing atomic accuracy for structural predictions for homology modellers better than a typical modeller could produce.

This paper is mainly a flag planted so they can claim they landed on mars first and fastest.

[eganp]

There a quite a few things missing from this paper that would make it a good a good drug discovery paper.

First, they didn't discover a drug - they found a hit. 30 days from target to hit using conventional high-throughput biochemical screening would take 2-4 months. So, this is 3x faster, but that's not the rate limiting step. Validation and in vivo studies will take >4 mo and 1-12mo respectively.

Second, if we take this as a "we found a hit" paper, I want to know how specific your hit is. This would be one of the major advantages of using AF2 - screen against related proteins with some structural or functional similarity. This is the time intensive and oft overlooked part of good in vitro screening campaigns. Potency is nice (although 9 μM isn't impressive), but ultimately selectivity is paramount when targeting a class of proteins with well conserved binding sites, like kinases. If they found a promiscuous CDK inhibitor that happens to hit CDK20, then I bet there are tons of previously reported promiscuous CDK inhibitors that will hit CDK20 too.

Third, this paper is surprising because it exploits none of the cool new things AF2 could enable. In addition to what you mention above, the authors could have tried to counter screen (much faster in silico!), find an allosteric inhibitor, identify a PPI/complex inhibitor, or take a leap by generating a SAR series in silico and validating a few selected compounds in vitro.

Overall, this paper seems both incremental and misdirected. Saving 2 months in the discovery phase, pre-IP, is worth ~0. Not sure anyone there has much experience developing drugs. Hits are nice, but rarely the hard part. However, a hit on a protein from a structurally divergent class would be a major accomplishment.

[jeejayisbusy]

another important point to notice is affinity. While 8 uM looks impressive, it is not that hard to develop such potency since compounds are likely to aim ATP binding pocket. It is big, deep and offers many hydrogen bond donors in hindge region. What important for such compounds is selectivity, since you want to inhibit only specific kinase, not all of them. For me it looks like advertising of their platform, not actual scientific achievement.

[SubiculumCode]

And this, dear HN community, is the difference between an expert reading a paper pertaining to their field and the casual reader, or even scientists in unrelated fields reading this paper. I am just not equipped to judge the quality of research in the field.