In 2009 we highlighted a paper reporting
that approved drugs have a higher fraction of sp3-hybridized
carbon atoms than discovery-phase compounds. Perhaps focusing on molecules with a
high Fsp3, the ratio of sp3-hybridzed carbons to
total carbons, would lead to greater success. Or not: a new analysis in Nat.
Rev. Chem. by Ian Churcher (Janus Drug Discovery), Stuart Newbold, and
Christopher Murray (both at Astex) finds that the relationship has not held up.
The 2009 “Escape from Flatland”
paper was widely discussed at conferences and has been cited more than 3000 times.
But according to the authors of the new study, most of these citations are from
papers describing new synthetic methodologies rather than from papers
discussing medicinal chemistry.
And not all the attention has been positive. As we noted in 2013, Pete Kenny and Carlos Montanari reanalyzed
the data and found that an apparent correlation between Fsp3 and
solubility disappeared when plotting all discrete data points instead of binned data.
More recently, we highlighted a paper
that found no significant difference between the shapeliness of drugs, as assessed
by their principal moment of inertia (PMI), and the shapeliness of small
molecules in the ZINC database.
The new paper looks at Fsp3
values for drugs approved during various time periods. Among 980 drugs approved
up to 2009, the average Fsp3 was 0.458. However, of the 431 drugs
approved after 2009, the average Fsp3 has dropped to 0.392. The
researchers speculate that this (statistically significant) decrease may be due
to an increase in the number of kinase inhibitors, which are usually highly
aromatic, as well as an increase in the use of metal-catalyzed cross coupling
reactions.
In my analysis of the 2009
paper, I asked whether higher Fsp3 ratios would lead to lower hit
rates, and indeed this seems to be the case, as shown in a paper we discussed in 2020. Thus, if you pursue difficult targets, you may increase your chances of finding hits by screening molecules with lower Fsp3 ratios. Also, multiple studies, including one published just last month, have found
no correlation between the shapeliness of a fragment (as defined by deviation
from planarity, or DFP) and the shapeliness of the resulting lead, so there appears to be no penalty to starting with a flattish fragment.
The researchers conclude that their
“analysis of drug development trends over the last 15 years suggests that Fsp3
may not have been a useful metric to optimize.” Importantly, the supplementary
information includes a list of >1400 approved drugs and >1500
investigational drugs along with associated properties, so you can do your own
analyses.
In the end, generalizations
will only get you so far, and may even lead you astray. At least for now, there
are few shortcuts in the long slog of experimental studies necessary to discover a drug.
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2 comments:
I agree with the authors' speculation that the overall decrease is "due to an increase in the number of kinase inhibitors", which are flat. The appropriate 3D-ness of a screening library depends on the target. For a protein-protein interaction target, I believe that increased 3D-ness will increase the odds of finding good leads (although it may decrease the hit rate. I'd rather have good leads than a high hit rate.)
Thanks for the summary dan. One other aspect I hear in favour of chirality is selectivity - presumably chiral molecules have more complex shapes and thus fewer off targets, so one might willingly pay the cost of a lower hit rate. For kinases in oncology, perhaps off-targets are (relatively) of less concern given the urgency or the treatment, so 3d-ness doesnt matter
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