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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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April 11, 2013

Fragments For Receptors: It Can Be Done

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Posted by Derek

The advent of real X-ray structures for receptors means that there are many experimental approaches that can now be tried that earlier would have been (most likely) foolhardy. My first research in the industry was on dopamine receptors, which I followed up by a stint on muscarinics, and we really did try to be rational drug designers. But that meant homology models and single-point mutations, and neither of those was always as helpful as you'd like. OK, fine: neither of them were very helpful at all, when you got right down to it. We kept trying to understand how our compounds were binding, but outside of the obvious GPCR features - gotta have a basic amine down there - we didn't get very far.

That's not to say that we didn't make potent, selective compounds. We certainly did, although you'll note that I'm not using the word "drug". For many of them, even the phrase "plausible clinical candidate" is difficult to get out with a straight face, potent and selective though they may have been. We made all these compounds, though, the old-fashioned way: straight SAR, add this on and take that away, fill out the table. Structural biology insights didn't really drive things much.

So when the transmembrane receptor X-ray structures began to show up, my first thought was whether or not they would have helped in that earlier effort, or whether they still had enough rough edges that they might have just helped to mislead us into thinking that we had things more figured out. There's a report, though, in the latest J. Med. Chem. that puts such structures to a pretty good test: can you use them to do fragment-based drug discovery?

Apparently so, at least up to the point described. This is the most complete example yet reproted of FBDD on a G-protein coupled receptor (beta-1 adrenergic). Given the prominence of receptors as drug targets, the late advent of fragment work in this field should tell you something about how important it is to have good structural information for a fragment campaign. I'm not sure if I've ever heard of one being successful without it - people say that it can be done, but I certainly wouldn't want to be the person doing it. That's not to say that X-ray structures are some sort of magic wand (this review should disabuse a person of that notion) - just that they're "necessary, but not sufficient" for getting a fragment program moving at reasonable speed. Otherwise, the amount of fumbling around at the edge of assay detection limits would be hard to take.

The beta-adrenergic receptor is the one with the most X-ray data available, with several different varieties of agonists and antagonists solved. So if any GPCR is going to get the fragment treatment, this would be the one. (There's also been a recent report of a fragment found for an adenosine receptor, which was largely arrived at through virtual screening). In this case, the initial screening was done via SPR (itself a very non-trivial technique for this sort of thing), followed by high-concentration radioligand assays, and eventual X-ray structure. They found a series of arylpiperazines, which are thoroughly believable as GPCR hits, although they don't have much of a history at the adrenergic receptor itself. The compounds are probably antagonists, mainly because they aren't making enough interactions to flip the switch to agonist, or not yet.

This paper only takes things up to this point, which is still a lot farther than anyone would have imagined a few years ago. My guess is that FBDD is still not ready for the spotlight in this field, though. This paper is from Miles Congreve and the folks at Heptares, world experts in GPCR crystallography, and presumably represents something pretty close to the state of the art. It's a proof-of-concept piece, but until the structures of more difficult receptors are available with more regularity, I don't think we'll see too much fragment work in the area. I'd be happy to be wrong about that.

Comments (7) + TrackBacks (0) | Category: Drug Assays


1. NOLAACS on April 11, 2013 9:48 AM writes...

They gave an oral presentation on this work at the New Orleans MEDI oral general session on Tuesday morning. I'm not an expert in the field but I thought the presentation was very good. In fact as a side note, I thought the entire oral session was good!

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2. petros on April 11, 2013 10:12 AM writes...

Miles and his colleagues have been doing this for a while. The B1AR is just a model system for them to describe their methodology in more detail. Accordingly its tended to be SAR by catalogue.

But they have presented details of some of the fragments they've screened using SPR and ZoBio's TINS (NMR) assays for the A2a receptor, which has led to novel development candidates.

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3. Chris Swain on April 11, 2013 1:51 PM writes...

At the Fragments meeting in Oxford there were posters/presentations describing work at Beta2, A2A, and two on the histamine H1.

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4. Teddy Z on April 11, 2013 3:42 PM writes...

Also, note that this is on the STAR receptors, so these are stabilized GPCRs, which means only Heptares can do it this way. With that caveat, Receptos in SD is also doing GPCR X-ray crystallography. I saw them speak at a conference in Boston last year. I still aver that you can successfully prosecute fragments without X-ray data, you just need to be flexible in terms of what kind of "structural" data you use.

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5. cliffintokyo on April 13, 2013 4:35 AM writes...

It is good to see this type of study of FBDD and applications to GPCRs being published and discussed. Hope to see more soon.

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6. cliffintokyo on April 13, 2013 4:36 AM writes...

It is good to see this type of study of FBDD and applications to GPCRs being published and discussed. Hope to see more soon.

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7. Frank on April 13, 2013 10:51 AM writes...

This is a great paper on a model system.
However- I think this kind of work is somewhat oversold in terms of drug discovery usefulness.

The beta adrenergic receptors are fairly easy to drug using standard methods- I don't know the numbers but there are in the order of 20-50 approved drugs that target these receptors. 50 years of work on this topic.

This subfamily of receptors already binds fragments with high affinity. Adrenaline is 180 MW and interacts with low nM affinity.

So having success with fragments on this target- well it doesn't convince me that fragments are necessarily the way to go for GPCRs.

Show me that fragment screening and/or structural biology can enable a receptor where we have poor chemical matter e.g. peptide receptors or poor orthosteric selectivity (muscarinics). This is the gap in GPCR drug discovery that currently exists- not the ability to find new chemotypes for monoamine receptors.

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