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Derek Lowe The 2002 Model

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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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June 25, 2014

Where's the Widest Variety of Chemical Matter?

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Posted by Derek

A look through some of the medicinal chemistry literature this morning got me to thinking: does anyone have any idea of which drug target has the most different/diverse chemical matter that's been reported against it? I realize that different scaffolds are in the eye of the beholder, so it's going to be impossible to come up with any exact counts. But I think that all the sulfonamides that hit carbonic anhydrase, for example, should for this purpose be lumped together: that interaction with the zinc is crucial, and everything else follows after. Non-sulfonamide CA inhibitors would each form a new class for each new zinc-interacting motif, and any compounds that don't hit the zinc at all (are there any?) would add to the list, too. Then you have allosteric compounds, which are necessarily going to look different than active-site inhibitors.

My guess is that some of the nuclear receptors would turn out to win this competition. They can have large, flexible binding pockets that seem to recognize a variety of chemotypes. So maybe this question should be divided up a bit more:

1. What enzyme is known to have the widest chemical variety of active-site inhibitors?

2. Which GPCR has the widest chemical variety of agonists? Antagonists? (The antagonists are going to win this one, surely).

3. And the the open field question asked above: what drug target of any kind has had the widest variety of molecules reported to act on it, in any fashion?

I don't imagine that we'll come to any definitive answer to any of these, but some people may have interesting nominations.

Update: in response to a query in the comments, maybe we should exempt the drug-metabolizing enzymes from the competition, since their whole reason for living is to take on a wide variety of unknown chemical structures.

Comments (25) + TrackBacks (0) | Category: Chemical News | Drug Assays


1. Erebus on June 25, 2014 11:39 AM writes...

2. If I had to venture a guess, I'd probably say Histamine H1. It has many dozens of inhibitors. Interestingly, the H4 receptor is at the far other end of the spectrum, with very few agonists/antagonists known to science.

3. Is CYP3A4 a 'drug target', for the sake of this debate?

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2. a. nonymaus on June 25, 2014 11:56 AM writes...

I'd guess that for question 2, the answer is the cannabinoid receptor. You've got long-chain ethanolamides, the cannabinoids themselves, yangonin, cyclohexylphenol synthetics, aroylindoles and pyrroles, this, that, the other... let alone the various antagonists and inverse agonists that have trod the med-chem stage.

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3. Vladimir Chupakhin on June 25, 2014 12:26 PM writes...

the most studied will be the most diverse - GPCRs, kinases - common list.

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4. Anonymous on June 25, 2014 12:40 PM writes...

"which drug target has the most different/diverse chemical matter that's been reported against it"

Amyloid, I'm absolutely certain of it. Check out a review of reported "inhibitors", and you'll see everything from propanesulfonic acid to curcumin, to sugar derivatives, to short peptides, to whole antibodies.

EVERYTHING inhibits amyloid, it seems, even in mice.

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5. rico on June 25, 2014 12:47 PM writes...

if you stick to only approved drugs, a GPCRs is the likely 'winner'.

if we are more loose with the parameters - Tubulin.

Taxol, vinca alkaloids, colchine, eribulin (halochondrin B), ixebepolone (epithilone) - all approved drugs. beyond that, for both stabilizing and destabilizing the microtubule filaments, the variety of chemical matter that does this is astounding.

Combrestatins, kinase inhibitor scaffolds, nocodazole, discodermolides, and about 10 other diverse classes of natural products.

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6. SteveM on June 25, 2014 12:54 PM writes...

Mapping the links between molecular classes and target enzymes sounds like a good IBM Watson project. Although I suppose there would be lot of grunt work to enter basic interaction data so at least semi-quantitative relationships could be queried.

P.S. There is an interesting non-relational database technology called Topic Maps that would be perfect for this application because the user interface is visual.

P.P.S. Maybe get NSA to do it. They got plenty of dough to waste.

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7. bhip on June 25, 2014 1:23 PM writes...

Speaking from the GPCR screening perspective, I found cannabinoid CB2 (see Anon 2 above) & adenosine A3 were the most promiscuous GPCR, collecting both leads & garbage with equal acumen.

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8. NUchemist on June 25, 2014 1:28 PM writes...

The μ-opioid receptor should definitely be a candidate. Med chemists have cranked out a vast array of different scaffolds that can bind to it (heroin, fentanyl, meperidine, methadone, etc.)

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9. anon on June 25, 2014 1:55 PM writes...

@1 - 3

HIV drugs have had "boosters" - which mainly inhibit CYP3A4-- +

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10. Curious Wavefunction on June 25, 2014 1:59 PM writes...

I don't know the answer but I would generally look at enzymes with large and/or conformationally mobile binding sites. Also, while it's not an enzyme, I would think serum albumin is incredibly promiscuous in its interactions with a variety of chemical scaffolds.

I would also second #5's choice of tubulin; it has at least three binding sites and binds to a very diverse set of compounds ranging from the simple alkaloid noscapine (an antitussive compound in cough syrup) to dictyostatin (a complex macrocycle).

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11. DCRogers on June 25, 2014 2:36 PM writes...

Not exactly what you asked for, but I read a version of MDDR with activity class information, calculated the molecular fingerprint ECFP_6 to represent the features that define "differentness", and counted the number of different ECFP_6 bits per activity class.

Drum roll, please:

  1. Antineoplastic: 218692
  2. Antiarthritic: 113710
  3. Antiallergic/antiasthamatic: 93029
  4. Antihypertensive: 89700
  5. Antidiabetic: 78815
  6. Analgesic, non-opiod: 75297
  7. Cognition disorders: 74509
  8. Anxiolytic: 72130
  9. Hypolipidemic: 69551
  10. Andidepressant: 67693

So to me, this suggests that most of the major expected areas of work have been diversely tested against.

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12. Humpty on June 25, 2014 3:02 PM writes...

I would put my money on a GPCR selected through evolution for ligand promiscuity, such as a member of the bitter taste receptor family.

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13. ScientistSailor on June 25, 2014 3:35 PM writes...

If we limit ourselves to a single target, for the sake of simplicity, 11-bHSD has very diverse set of inhibitors.

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14. Bryan on June 25, 2014 3:49 PM writes...

The ribosome has probably got to be up there just because it's such a large molecule and there are so many different steps (e.g. initiation, aminoacyl-tRNA binding, peptidyl transfer, translocation, termination) that different antibiotics target.

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15. Rock on June 25, 2014 5:40 PM writes...

For #1 my nomination would be PDE4.

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16. Anonymous on June 25, 2014 7:10 PM writes...

What about Cyp's? Those things seem to chew on everything I throw at them...

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17. CK on June 26, 2014 6:34 AM writes...

not really targets, but rather off-targets that recognize a wide diversity of structures:

- hERG channels
- ABC transporters

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18. MoBio on June 26, 2014 8:42 AM writes...

Sigma 'receptors'... virtually anything 'druglike' interacts with these with sum uM affinity.

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19. JAB on June 26, 2014 8:48 AM writes...

I have to agree with Rico about tubulin, not for approved drugs but for all known ligands. I've added several myself: flavones and chamaecypanone. I think it's mostly a function of how large the target is and how much effort has gone into looking.

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20. tristan on June 26, 2014 1:33 PM writes...

Nature came up with a wide variety of inhibitors of the ribosome. Then chemists came up with some more.

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21. JKB on June 27, 2014 3:19 PM writes...

How tightly do you want to define "drug target"? I would think that the range from cis-platin and its cousins to doxorubicin to paclitaxel to duocarmycins and on and on make DNA a target with a remarkable variety of drugs that act on it, in one way or another.

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22. in vivo veritas on June 27, 2014 3:28 PM writes...

The sigma-1 receptor for sure. No one knows what it really does but it's included in the standard selectivity binding panels.

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23. Jay Bradner on June 28, 2014 2:17 PM writes...

We had this discussion at group meeting a few months ago. It is also interesting to consider diversity per unit of time the field has spent intently prosecuting the target. Here BRD4 starts looking fairly competitive even against the tubulins and GPCRs of the world!

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24. Secondaire on June 28, 2014 6:42 PM writes...

#16 - seriously. You put an imidazole on damn near anything and it's a CYP inhibitor.

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25. RBW on July 7, 2014 1:25 PM writes...

What about HIV reverse transcriptase? A large enzyme with multiple functions and you see a diversity of structural motifs among non-nucleoside RT inhibitors.
I would argue that many of the targets discussed above did not yield that much diversity...opioid ligands have a similarity in pharmacophore as do the 1001 heterocycles that target ATP binding sites.

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