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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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July 16, 2008

Receptors: Can't Live With 'Em, Can't Understand 'Em

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Posted by Derek

At various points in my drug discovery career, I’ve worked on G-protein-coupled receptor (GPCR) targets. Most everyone in the drug industry has at some point – a significant fraction of the known drugs work through them, even though we have a heck of a time knowing what their structures are like.

For those outside the field, GPCRs are a ubiquitous mode of signaling between the interior of a cell and what’s going on outside it, which accounts for the hundreds of different types of the things. They’re all large proteins that sit in the cell membrane, looped around so that some of their surfaces are on the outside and some poke through to the inside. The outside folds have a defined binding site for some particular ligand - a small molecule or protein – and the inside surfaces interact with a variety of other signaling proteins, first among them being the G-proteins of the name. When a receptor’s ligand binds from the outside, that sets off some sort of big shape change. The protein’s coils slide and shift around in response, which changes its exposed surfaces and binding patterns on the inside face. Suddenly different proteins are bound and released there, which sets off the various chemical signaling cascades inside the cell.

The reason we like GPCRs is that many of them have binding sites for small molecules, like the neurotransmitters. Dopamine, serotonin, acetylcholine – these are molecules that medicinal chemists can really get their hands around. The receptors that bind whole other proteins as external ligands are definitely a tougher bunch to work with, but we’ve still found many small molecules that will interact with some of them.

Naturally, there are at least two modes of signaling a GPCR can engage in: on and off. A ligand that comes in and sets off the intracellular signaling is called an agonist, and one that binds but doesn’t set off those signals is called an antagonist. Antagonist molecules will also gum up the works and block agonists from doing their things. We have an easier time making those, naturally, since there are dozens of ways to mess up a process compared to the ways there are of running it correctly!

Now, when I was first working in the GPCR field almost twenty years ago, it was reasonably straightforward. You had your agonists and you had your antagonists – well, OK, there were those irritating partial agonists, true. Those things set off the desired cellular signal, but never at the levels that a full agonist would, for some reason. And there were a lot of odd behaviors that no one quite knew how to explain, but we tried to not let those bother us.

These days, it’s become clear that GPCRs are not so simple. There appear to be some, for example, whose default setting is “on”, with no agonist needed. People are still arguing about how many receptors do this in the wild, but there seems little doubt that it does go on. These constituitively active receptors can be turned off, though, by the binding of some ligands, which are known as inverse agonists, and there are others, good old antagonists, that can block the action of the inverse agonists. Figuring out which receptors do this sort of thing - and which drugs - is a full time job for a lot of people.

It’s also been appreciated in recent years that GPCRs don’t just float around by themselves on the cell surface. Many of them interact with other nearby receptors, binding side-by-side with them, and their activities can vary depending on the environment they’re in. The search is on for compounds that will recognize receptor dimers over the good ol’ monomeric forms, and the search is also on for figuring out what those will do once we have them. To add to the fun, these various dimers can be with other receptors of their own kind (homodimers) or with totally different ones, some from different families entirely (heterodimers). This area of research is definitely heating up.

And recently, I came across a paper which looked at how a standard GPCR can respond differently to an agonist depending on where it's located in the membrane. We're starting to understand how heterogeneous the lipids in that membrane are, and that receptors can move from one domain to another depending on what's binding to them (either on their outside or inside faces). The techniques to study this kind of thing are not trivial, to put it mildly, and we're only just getting started on figuring out what's going on out there in the real world in real time. Doubtless many bizarre surprises await.

So, once again, the "nothing is simple" rule prevails. This kind of thing is why I can't completely succumb to the gloom that sometimes spreads over the industry. There's just so much that we don't know, and so much to work on, and so many people that need what we're trying to discover, that I can't believe that the whole enterprise is in as much trouble as (sometimes) it seems. . .

Comments (20) + TrackBacks (0) | Category: Biological News | Drug Assays


1. Still Scared of Dinosaurs on July 16, 2008 9:48 AM writes...

The degree of complexity finally shorted a few of my neurons when a colleague explained that the receptor we were hitting was contained inside the cell - the drug had to be taken in by other mechanisms and processed inside a protected space within the cell. Not sure if these qualify as GPCRs because I had to stop asking questions for a while and recuperate.

Anybody know where you can go to get a degree in membranomics?

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2. smurf on July 16, 2008 1:06 PM writes...

The bad news is: ion channels are even more complicated.

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3. Derek Lowe on July 16, 2008 1:50 PM writes...

Sad, but absolutely true. Ion channels make GPCRs look completely sensible. . .

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4. ZAL on July 16, 2008 4:05 PM writes...

Congratulations for the excellent article! I just started to look into the world of agonists and antagonists to get myself prepared for a job interview, but I didn't imagine things were so complicated!

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5. Shane on July 16, 2008 7:16 PM writes...

It makes you really reflect on whether or not all this molecular and mechanistic level of information is really useful in the long run. In the end your drug has to function in the whole organism, so why not just figure out an ethical way to screen the whole organism from the beginning? The old days of drug discovery tended to do this and they seem to have had a better chance of finding drugs, albeit at random rather than on purpose. Better to find an effective drug at random than a poor drug deliberately?

If only we had little homimems floating in our test long as there weren't little lawyers or hominem rights activists in there too.....

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6. DrSnowboard on July 17, 2008 4:23 AM writes...

It's all right, the visionary management consultants tell us computers will sort it out by 2020.

After all no one listened to them when they said biologics was the future for 2010...Oh no, they did.

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7. daen on July 17, 2008 6:11 AM writes...

Thank you Dr Snowboard for providing some light reading that veers wildly and incoherently from far-out sci-fi (nanobots monitoring my vital signs, indeed) to the mundane (CTD for new submissions). Just goes to show that PwC are just as confused as anyone else. Also, note that these views are "personnal" on the credits page ... always reassuring that a multi-billion dollar consultancy marketing to a multi-billion dollar industry can't be bothered to proofread its documents.

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8. Still Scared of Dinosaurs on July 17, 2008 6:25 AM writes...

Ion Channels? Isn't that what the Rebel Alliance used to protect the ships escaping the ice planet Hoth?

And wouldn't that be homunculii in the test tubes, or is that term reserved for the pilots of sperm cells and Wallace Shawn? One approximation of that is the use of human cell lines. Since I don't even have a job until variability comes into play I wonder how useful it has proven to test NCEs against lines from the broadest set of original donors. Would it help to select the donors - highly allergic, resistant to viral diseases, good sense of humor - to highlight specific concerns. I understand that cells aren't people, and immortalized cell lines aren't really people cells anymore, but I'm just wunnerin'...

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9. befuddled on July 17, 2008 7:28 AM writes...


They certainly use cell lines (human and otherwise) in pharma research. Personally, I think the next big step will the be use of (human-derived) tissues and organoids that more closely approximate normal tissues. Recent progress with stem cells and tissue engineering is very encouraging in that regard.

And, as you say it will be necessary to use "recombinant" tissues from a large variety of donors (though I think those with a good sense of humor will, as always, be in short supply) for reliable results.

Of course, even then we'll have issues with pharmacokinetics, metabolic activation and de-activation, etc.

BTW, does anyone have a handle on the percentage of approved drugs whose activity is based on a metabolite, especially those for which that fact was only discovered late in development?

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10. ClinPharm'ist on July 17, 2008 7:31 AM writes...

I'm with Shane re the complexity of biology. I have spent the last 20 years taking new small molecules and engineered proteins into man and my major insight is, unless the compound in question is a very close me-too for a compound with a clinically validated mechanism, then you had better be very well prepared for surprises whatever the preclinical package says.

The pre-clinical in vivo systems we have model complexity quite well, but in the wrong species and the available in silico techniques require us to make predictions from simplistic and incomplete datasets. My current approach is to require assessment of the activity of a compound in explant human tissues or structured co-culture systems (not single cells) relevant to the disease of interest prior to entry into man but I'm not kidding myself that this will be the holy grail.

Which brings us back to Derek's final comment on things in the industry not being as bad as all that. I agree that there is a vast amount to learn and, having learned it, a vast amount of misery to alleviate/money to be made. It is the vast (and increasing) amount of investment required to get from the one to the other that bothers me.

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11. Jose on July 17, 2008 9:15 AM writes...

The PWC Pharma 2020 package is amazing. Virtual organisms! Instantaneous FDA e-approval! Seamless R&D! Perfectly validated mechanisms! Geee, I can't wait; will Tom Swift be there with a space-ray, too?

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12. FormerMolecModeler on July 17, 2008 10:51 AM writes...

How much would it cost to run a low-throughput screen of say 10K compounds using mice instead of cells or plates?

You'd need enough of each compound for 10K mice though...hmm would be pricey. Also you'd probably want to run at 3 different doses. So what, $100M? $200M?

Risky, but it might just work! :)

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13. Skeptic on July 17, 2008 1:21 PM writes...

Shane: "It makes you really reflect on whether or not all this molecular and mechanistic level of information is really useful in the long run"

Sydney Brenner Interview
Nature Reviews Molecular Cell Biology January 2008

"How has molecular biology research changed in the past 50 years?

It has changed completely. It has become much more descriptive and much less experimental. It is what I call ‘low input, high throughput, no output science’! The proponents of this kind of science claim that by generating descriptions of the behaviour of biological systems they’ll be able to generate models of what’s going on in them, and then refine these models. They call this ‘systems biology’. To use a simple analogy of this type of science, consider that one is sitting outside a room in which someone is playing a drum. The room is wired for sound, and using only the recording of
the sounds one is trying to reconstitute the
physical properties of the drum. In my mind one cannot succeed because in this classic inverse problem, information is lost and measurements are inaccurate. The best thing to do is to tackle the problem directly by studying the drum — then one can play it oneself. That is what molecular biology is about. It is mechanism based and causation based. But nowadays scientists aren’t asking as many mechanistic and causative questions."

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14. tgibbs on July 17, 2008 3:00 PM writes...

And to make things worse, there is some evidence that ion channels can cozy up to GPCRs with crosstalk going back and forth.

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15. retread on July 17, 2008 8:59 PM writes...

" There's just so much that we don't know, and so much to work on. "


For some ideas about just how vast our ignorance is, and just how complex the system we're dealing with actually is, see the following two posts under "Chemiotics" in "The Skeptical Chymist"

15 May '08 -- "Do you know where your drug is . . .
3 April '08 -- "Causality in the cell . . .

If you could follow Derek's excellent exposition of GPCRs, you shouldn't have any trouble with them.

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16. Anonymous BMS Researcher on July 17, 2008 10:49 PM writes...

smurf on July 16, 2008 1:06 PM wrote...

> The bad news is: ion channels are even
> more complicated.

Shall we hold a vote for favorite target class?
I'd vote for GPCR's -- not only do they represent a hefty chunk of our industry's income, but also I've worked on them off and on since about 1994 so I'm about as familiar with them as I am with any target class, not that anybody has much of a clue what orphan GPCRs do. Much of the pharmacology is in those big floppy loops, but most of what we know about their structures pertains mostly to those seven transmembrane domains. If I've mapped a mutation of interest to, say, somewhere on intracellular loop between TM3 and TM4, then I'm sorta stuck so far as structural biology goes! Even the lengths of those loops varies so much between types of GPCR that homology modeling is rather questionable.

Here's another class that can be lots of fun:

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17. Undiagnosed on July 19, 2008 1:42 AM writes...

Very interesting article.
I know they are needed but I could sure do without my receptors at the moment

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18. Jonadab the Unsightly One on July 19, 2008 7:58 AM writes...

What's already going on inside the cell might also have an impact on what happens (inside the cell) when an agonist molecule binds a GPCR on the outside. And what's going on inside the cell, chemically speaking, probably depends at least partly on what else is bound to other receptors elsewhere on the outside of the membrane...

A living organism is not a set of straightforwardly independent reactions that don't affect one another. Quite the contrary.

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19. Retread on July 19, 2008 11:08 AM writes...

Jonadab the Unsightly One:

Excellent comment

"What's already going on inside the cell might also have an impact"

Well, I wouldn't say might. It's almost Heraclitan -- you never step in the same river twice, and likely no two cells (even ones the experimentalist has attempted to synchronize) have exactly the same internal state (assuming you can even define the internal state of a cell given what we know about cells presently).

Another class of surface receptor (called integrins) are known to signal both ways (from the outside in and from the inside of the cell outwards). See [ Nature vol. 437 pp. 426 - 431 '05 ] for an example of the latter. For a good initial description of the integrins see "Molecular Biology of the Cell" by Alberts -- in the 4th edition the discussion starts on p. 1113 (but there is 5th edition out presently)

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20. Ken Rubenstein on August 1, 2008 3:30 PM writes...

And you haven't even mentioned the currently superhot area of GPCR allosteric modulators. Lots of possible advantages, but they tend to be on the hydrophobic side. Check out Jeffrey Conn's work at Vanderbilt and the company Addex.

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