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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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May 28, 2014

The Science Chemogenomics Paper is Revised

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Posted by Derek

The Science paper on chemogenomic signatures that I went on about at great length has been revised. Figure 2, which drove me and every other chemist who saw it up the wall, has been completely reworked:

To improve clarity, the authors revised Fig. 2 by (i) illustrating the substitution sites of fragments; (ii) labeling fragments numerically for reference to supplementary materials containing details about their derivation; and (iii) representing the dominant tautomers of signature compounds. The authors also discovered an error in their fragment generation software that, when corrected, resulted in slightly fewer enriched fragments being identified. In the revised Fig. 2, they removed redundant substructures and, where applicable, illustrated larger substructures containing the enriched fragment common among signature compounds.

Looking it over in the revised version, it is indeed much improved. The chemical structures now look like chemical structures, and some of the more offensive "pharmacophores" (like tetrahydrofuran) have now disappeared. Several figures and tables have been added to the supplementary material to highlight where these fragments are in the active compounds (Figure S25, an especially large addition), and to cross-index things more thoroughly.

So the most teeth-gritting parts of the paper have been reworked, and that's a good thing. I definitely appreciate the work that the authors have put into making the work more accurate and interpretable, although these things really should have been caught earlier in the process.

Looking over the new Figure S25, though, you can still see what I think are the underlying problems with the entire study. That's the one where "Fragments that are significantly enriched in specific sets of signature compounds (FDR ≤ 0.1 and signature compounds fraction ≥ 0.2) are highlighted in blue within the relevant signature compounds. . .". It's a good idea to put something like that in there, but the annotations are a bit odd. For example, the compounds flagged as "6_cell wall" have their common pyridines highlighted, even though there's a common heterocyclic core that that all but one those pyridines are attached to (it only varies by alkyl substitutents). That single outlier compound seems to be the reason that the whole heterocycle isn't colored in - but there are plenty of other monosubstituted pyridines on the list that have completely different signatures, so it's not like "monosubstituted pyridine" carries much weight. Meanwhile, the next set ("7_cell wall") has more of the exact same series of heterocycles, but in this case, it's just the core heterocycle that's shaded in. That seems to be because one of them is a 2-substituted isomer, while the others are all 3-substituted, so the software just ignores them in favor of coloring in the central ring.

The same thing happens with "8_ubiquinone biosynthesis and proteosome". What gets shaded in is an adamantane ring, even though every single one of the compounds is also a Schiff base imine (which is a lot more likely to be doing something than the adamantane). But that functional group gets no recognition from the software, because some of the aryl substitution patterns are different. One could just as easily have colored in the imine, though, which is what happens with the next category ("9_ubiquinone biosynthesis and proteosome"), where many of the same compounds show up again.

I won't go into more detail; the whole thing is like this. Just one more example: "12_iron homeostasis" features more monosubstituted pyridines being highlighted as the active fragment. But look at the list: there's are 3-aminopyridine pieces, 4-aminomethylpyridines, 3-carboxylpyridines, all of them substituted with all kinds of stuff. The only common thread, according to the annotation software, is "pyridine", but those are, believe me, all sorts of different pyridines. (And as the above example shows, it's not like pyridines form some sort of unique category in this data set, anyway).

So although the most eye-rolling features of this work have been cleaned up, the underlying medicinal chemistry is still pretty bizarre, at least to anyone who knows any medicinal chemistry. I hate to be this way, but I still don't see anyone getting an awful lot of use out of this.

Comments (6) + TrackBacks (0) | Category: Biological News | Chemical Biology | Chemical News | The Scientific Literature


1. Umpolung on May 28, 2014 10:29 AM writes...

Anything about the purity of their compounds, though? That was probably the biggest issue, in my mind.

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2. David Borhani on May 28, 2014 1:24 PM writes...

Nothing appears to be stated about purity, other than for the FDA-approved drugs ("highest purity available from commercial sources"), which constitute only 4% of the compound set. I checked a few of their commercial suppliers (Chembridge; TimTec). No purity info, though TimTec does state "NDL-3000 Compounds comply with screening purity standards," for what that's worth.

I agree with Derek that the paper still seems largely devoid of useful scientific content.

I know this may be beating a dead horse, but maybe, just maybe, one of the (senior) Authors will read this and other comments and be induced to emerge from their opium-induced fog?

Yet another example of the Authors' naïveté in Suppl. Fig. 25 is "31_calcium & mitochondrial duress". The "pharmacophore" is...drum roll... cyclohexane! Yes, Virginia, the cyclohexane ring at the center of the (very sugar-like) kanamycin is accorded the same pharmacophoric status as a cyclohexane (actually, a terpene, p-menthane) substituent on a series of (mostly) arylalkoxy-benzamidazoles.

The mere fact that the Authors deem the results of their "fragmentation" algorithm worthy of (lengthy) presentation in Suppl. Fig. 25 speaks volumes---they don't understand what makes a drug a drug.

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3. denton hoyer on May 28, 2014 3:09 PM writes...

There may be something of interest here that can be salvaged for the medicinal chemist. I'd like to see that small subset of drugs pulled out and examined, forget the rest. We would have more confidence in testing at soluble concentrations for a marketed drug and the information may just shed some light on off-target pharmacology and tox issues where any light is helpful.

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4. HT on May 29, 2014 12:25 AM writes...

As a biomedical researcher, I've learnt to respect the expertise of fellow chemists. In some past collaborations, there have been attempts for one side to 'teach' the other side how to do their job (e.g. chemists telling biologists how to do proper genetic analysis). These almost always end up in arguments, futility or disasters. I would classify the present Science paper in this category.

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5. Anonymous on May 29, 2014 4:17 AM writes...

There's a fine line between "teaching others in their own field how to do their job", and bringing in new ideas and a fresh perspective from outside to challenge conventional thinking and dogma within a field. The difference lies only in the true outcome, and is driven by pure chance as long as we are humble enough to accept that nobody really knows the truth until it is tested by experiment. After all, isn't that what science is all about? Otherwise we would still be in the dark ages, saying "how dare you try to teach us that the earth is not flat".

The authors of this paper may well be out of their depth, but I welcome their fresh perspective as it may spawn new ideas by experts within the field.

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6. Anonymous on May 29, 2014 10:46 AM writes...

@5: While that may be true, if your methodology is inherently flawed then it isn't helping anyone. You certainly won't be bringing a fresh perspective if other fields can't even trust the validity of your work.

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