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.
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.