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DBL%20Hendrix%20small.png College chemistry, 1983

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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August 20, 2013

GPCRs As Drug Targets: Nowhere Near Played Out

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Posted by Derek

Here's a paper that asks whether GPCRs are still a source of new targets. As you might guess, the answer is "Yes, indeed". (Here's a background post on this area from a few years ago, and here's my most recent look at the area).

It's been a famously productive field, but the distribution is pretty skewed:

From a total of 1479 underlying targets for the action of 1663 drugs, 109 (7%) were GPCRs or GPCR related (e.g., receptor-activity modifying proteins or RAMPs). This immediately reveals an issue: 26% of drugs target GPCRs, but they account for only 7% of the underlying targets. The results are heavily skewed by certain receptors that have far more than their “fair share” of drugs. The most commonly targeted receptors are as follows: histamine H1 (77 occurrences), α1A adrenergic (73), muscarinic M1 (72), dopamine D2 (62), muscarinic M2 (60), 5HT2a (59), α2A adrenergic (56), and muscarinic M3 (55)—notably, these are all aminergic GPCRs. Even the calculation that the available drugs exert their effects via 109 GPCR or GPCR-related targets is almost certainly an overestimate since it includes a fair proportion where there are only a very small number of active agents, and they all have a pharmacological action that is “unknown”; in truth, we have probably yet to discover an agent with a compelling activity at the target in question, let alone one with exactly the right pharmacology and appropriately tuned pharmacokinetics (PK), pharmacodynamics (PD), and selectivity to give clinical efficacy for our disease of choice. A prime example of this would be the eight metabotropic (mGluR) receptors, many of which have only been “drugged” according to this analysis due to the availability of the endogenous ligand (L-glutamic acid) as an approved nutraceutical. There are also a considerable number of targets for which the only known agents are peptides, rather than small molecules. . .

Of course, since we're dealing with cell-surface receptors, peptides (and full-sized proteins) have a better shot at becoming drugs in this space.

Of the 437 drugs found to target GPCRs, 21 are classified as “biotech” (i.e., biopharmaceuticals) with the rest as “small molecules.” However, that definition seems rather generous given that the molecular weight (MW) of the “small molecules” extends as high as 1623. Using a fairly modest threshold of MW <600 suggests that ~387 are more truly small molecules and ~50 are non–small molecules, being roughly an 80:20 split. Pursuing the 20%, while not being novel targets/mechanisms, could still provide important new oral/small-molecule medications with the comfort of excellent existing clinical validation. . .

The paper goes on to mention many other possible modes for drug action - allosteric modulators, GPCR homo- and heterodimerization, other GPCR-protein interactions, inverse agonists and the like, alternative signaling pathways other than the canonical G-proteins, and more. It's safe to say that all this will keep up busy for a long time to come, although working up reliable assays for some of these things is no small matter.

Comments (4) + TrackBacks (0) | Category: Biological News | Drug Assays


1. Anonymous on August 20, 2013 1:03 PM writes...

Say Derek, I have a question unrelated to this post. Sorry, I'm sure you get this every so often. What is up with this Corante site as a whole? Most of it seems dead other than your blog.


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2. sgcox on August 20, 2013 3:43 PM writes...

Easy. He makes drugs to keep it alive.

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3. petros on August 20, 2013 4:09 PM writes...

Class B & Class C GPCRs have barely been touched, partly attributable to the high number of orphan GPCRs in the former group. In class A once you go beyond the monoamine group successful exploitation has been sparse

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4. BTDT on August 20, 2013 7:42 PM writes...

Thank heavens for excellent in vivo pharmacologists - those are the folks that keep GPCR drug discovery alive and well.

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