Stuart Schreiber and Paul Clemons of the Broad Institute have a provocative paper out in JACS on natural products and their use in drug discovery. As many know, a good part of the current pharmacopeia is derived from natural product lead structures, and in many other cases a natural product was essential for identifying a target or pathway for a completely synthetic compound.
But are there as many of these cases as we think - or as there should be? This latest paper takes a large set of interaction data and tries to map natural product activities on to it. It's already know that there are genes all up and down the "interactome" spectrum, as you'd expect, with some that seem to be at the crossroads of dozens (or hundreds) of pathways, and others that are way out on the edges. And it's been found that disease targets tend to fall in the middle of this range, and not so much in the too-isolated or too-essential zones on either side.
That seems reasonable. But then comes the natural product activity overlay, and there the arguing can start. Natural products, the paper claims, tend to target the high-interaction essential targets at the expense of more specific disease targets. They're under-represented in the few-interaction group, and very much over-represented in the higher ones. Actually, that actually seems reasonable, too - most natural products are produced by organisms as essentially chemical warfare, and the harder they can hit, the better. Looking at subsets of the natural product list (only the most potent compounds, for example) did not make this effect vanish. Meanwhile, if you look at the list of approved drugs (minus the natural products on it), that group fits the middle-range interactivity group much more closely.
But what does that mean for natural products as drug leads? There would appear to be a mismatch here, with a higher likelihood of off-target effects and toxicity among a pure natural-product set. (The mismatch, to be more accurate, is between what we want exogenous chemicals to do versus what evolution has selected them to do). The paper ends up pointing out that additional sources of small molecules look to be needed outside of natural products themselves.
I'll agree with that. But I suspect that I don't agree with the implications. Schreiber has long been a proponent of "diversity-oriented synthesis" (DOS), and would seem to be making a case for it here without ever mentioning it by name. DOS is the idea of making large collections of very structurally diverse molecules, with an eye to covering as much chemical space as possible. My worries (expressed in that link above) are that the space it covers doesn't necessarily overlap very well with the space occupied by potential drugs, and that chemical space is too humungously roomy in any event to be attacked very well by brute force.
Schreiber made a pitch a few years ago for the technique, that time at the expense of small-molecule compound collections. He said that these were too simple to hit many useful targets, and now he's taking care of the natural product end of the spectrum by pointing out that they hit too many. DOS libraries, then, must be just in the right range? I wish he'd included data on some of them in this latest paper; it would be worthwhile to see where they fell in the interaction list.
1. bbooooooya on July 12, 2010 7:57 AM writes...
I've always felt that big pharma's foolish adherence to Lipinski's "rules" to be one of the reasons so few new drugs are discovered. Following after Lipinski, one seeks to discover new drugs by copying old drugs. This seems to me like Columbus seeking to discover India by sailing up the Rhine.
I don't entirely buy the "10^63" foolishiness that ws propagated a few years ago, but I think that looking at chemical spaces we've not been before is more likely to afford more interesting drugs than constantly reinventing the same heterocycles.
Of course, getting someone to pay for a dd program that would take a mimimum of 5 to 10 years to bear fruit could be an issue. I guess big pharma just prefers to play where it's been.
Permalink to Comment2. Mark on July 12, 2010 8:02 AM writes...
I would argue that natural products provide a cheap route to a lot of structure diversity. Who would want to be the chemist to have to synthesis morphine in order to discover the mu-opioid receptor?
Natural products themselves might not be the best drug, but they are a great tool to probe for useful structural elements that can be used to create more drugable candidates.
Mark
Permalink to Comment3. processchemist on July 12, 2010 8:04 AM writes...
"Genome biology is shining a bright light on the origins of human disease. Unfortunately, the biological targets emerging as ideal points for therapeutic intervention are often viewed as being extremely difficult, if not impossible, to modulate with small molecules "
Nature 457, 153-154 (8 January 2009)
IMHO some good modulations with small molecules have been achieved. Not so much maybe, but the kinome is probably the most drugged family of targets of ever, and some SM performed pretty well in the therapeutic use.
By the way, it will be great to see some translations from metachemistry to the real world, and to see how they perform.
Permalink to Comment4. newnickname on July 12, 2010 9:06 AM writes...
Also recently: Samuel Danishefsky, Nat. Prod. Rep., 2010, DOI: 10.1039/c003211p "On the potential of natural products in the discovery of pharma leads: A case for reassessment."
Basically, natural products are valuable leads and deliberately diverting synthetic intermediates (from a total synthesis) can produce greater quantities of superior candidates.
Permalink to Comment5. CMCguy on July 12, 2010 9:10 AM writes...
Are natural products really still a source of new drugs anymore? Once this was a prime area for leads and even drugs but has lost so much emphasis in academia and more so industry that sadly potential contribution is no longer every meaningful. Maybe ventures in Biologics have supplanted some of that utilization of nature in a that sense rather then small molecules from biologic chemical factories.
Conceptually DOS might hold promise to look in chemical places that are not normally explored which is worthwhile however translations to actual treatments may be more difficult as may also carry along new problems. There are practical aspects that must be considered, which largely comes from experiences medchemistry skills then continues through development. Although #1 can criticize Lipinki's "rules" which may indeed have inhibited some efforts due to over application if they are taken like the Pirate Codes as "Guidlines" and applied properly can help avoid certain pitfalls.
Permalink to Comment6. JRnonchemist on July 12, 2010 9:36 AM writes...
Stupid question: Maybe he isn't selling his existing library. Couldn't he be trying to isolate the portion of chemical space people should focus on if they are trying to make libraries of synthetic chemicals useful for drug discovery?
Permalink to Comment7. Hap on July 12, 2010 9:42 AM writes...
I wonder if a problem with small molecule leads is their inherent selectivities for receptors rather than their ability to hit receptors with the appropriate connectivities for disease genes. [Are small molecule leads as selective for their receptors as natural product-derived leads, or is their no such relation?] For example, I thought that Lipitor couldn't just be hitting its designed target because of its antilipidemic effect - it has to be inhibiting/modulating something else. Particularly with protein-protein interactions, it may be difficult to inhibit them specifically with a small molecule (though maybe that's just reason to look more closely).
Permalink to Comment8. Hap on July 12, 2010 9:43 AM writes...
I wonder if a problem with small molecule leads is their inherent selectivities for receptors rather than their ability to hit receptors with the appropriate connectivities for disease genes. [Are small molecule leads as selective for their receptors as natural product-derived leads, or is their no such relation?] For example, I thought that Lipitor couldn't just be hitting its designed target because of its antilipidemic effect - it has to be inhibiting/modulating something else. Particularly with protein-protein interactions, it may be difficult to inhibit them specifically with a small molecule (though maybe that's just reason to look more closely).
Permalink to Comment9. milkshake on July 12, 2010 9:43 AM writes...
I doubt big pharma will do much in house natural product research anymore though it might still license it in - if the product is good and some academic group does all the synthesis and biology research work for them...
Permalink to Comment10. MLBpitcher_and_MedicinalChemist on July 12, 2010 9:48 AM writes...
Most of the low hanging fruit has already been discovered and medicinal chemistry are in competition with their previous creations, whether it is purely artificial based on only the knowledge of its target, or something refined through evolutionary chemical warfare like many antibiotics and rapamycin derivatives that target mTOR. Most of those drugs are going to go off patent anyway, so medicinal chemists would have to be ingenious enough to construct efficacious and safe molecules so they would be included in the formularies of health insurance companies and governments with ready access to generic drugs.
If I remember correctly, TKIs are not based on natural products and imatinib was discovered through rational drug design, not through a natural product derivative. All TKIs have basically the same motif (quinazoline).
Are natural product based drugs already picked low-hanging fruit that is about to go rotten due to the expiration of patents?
PS... Derek.. you lost against the Mets on Sunday giving up two runs in 5 1/3 innings. That sucks... Johan was just pwnd joo!!
Permalink to Comment11. MLBpitcher_and_MedicinalChemist on July 12, 2010 9:51 AM writes...
Most of the low hanging fruit has already been discovered and medicinal chemistry are in competition with their previous creations, whether it is purely artificial based on only the knowledge of its target, or something refined through evolutionary chemical warfare like many antibiotics and rapamycin derivatives that target mTOR. Most of those drugs are going to go off patent anyway, so medicinal chemists would have to be ingenious enough to construct efficacious and safe molecules so they would be included in the formularies of health insurance companies and governments with ready access to generic drugs.
If I remember correctly, TKIs are not based on natural products and imatinib was discovered through rational drug design, not through a natural product derivative. All TKIs have basically the same motif (quinazoline).
Are natural product based drugs already picked low-hanging fruit that is about to go rotten due to the expiration of patents?
PS... Derek.. you lost against the Mets on Sunday giving up two runs in 5 1/3 innings. That sucks... Johan was just pwnd joo!!
Permalink to Comment12. MedChem on July 12, 2010 10:00 AM writes...
#4 "Also recently: Samuel Danishefsky, Nat. Prod. Rep., 2010, DOI: 10.1039/c003211p "On the potential of natural products in the discovery of pharma leads: A case for reassessment."
Permalink to CommentFunny. Did you see Danishefsky's praise of this paper in C&EN? I guess they'd say whatever that fits the theme of the paper they're trying to publish at the time.
13. molecular architect on July 12, 2010 10:12 AM writes...
@MedChem: You should reread Danishefsky's "praise" of this paper. It's quite a cleverly worded back-handed compliment.
"Alas, as would have been expected from professor Schreiber ..."
Permalink to Comment14. RM on July 12, 2010 10:26 AM writes...
My thoughts can be summarized by misquoting Churchill:
"Natural products are the least reliable source of pharmaceuticals, except for all the others that have been tried."
Permalink to Comment15. MedChem on July 12, 2010 10:30 AM writes...
#13
That's a good one!
Permalink to Comment16. ronathan richardson on July 12, 2010 11:19 AM writes...
Seeing Schreiber talk recently, he bragged extensively about the DOS collection's ability to hit "untargetable" targets, by which he mainly meant transcription factors, based on small molecule microarray data. I had thought TF's were the main untargetable target that we would cure diseases (at least cancer) if we could hit the way we hit kinases, but that "network connectivity" view of things might change my mind--TF's are central network regulators usually.
Permalink to Comment17. Ed on July 12, 2010 11:55 AM writes...
Natural products are very much the first-choice go-to molecules when considering antibody drug conjugates.
To suggest that the field is dead based only on immediate personal experience seems somewhat arbitrary and disingenious.
Permalink to Comment18. milkshake on July 12, 2010 12:04 PM writes...
AML drug that is currently in the clinic (phase II) for a glutamate transporter boosting in MAL patients is actually working as a transcription factor - and it is a small molecule - a semisynthetic cefam analogue that is already approved as injectable antibiotics
Permalink to Comment19. MLBpitcher_and_MedicinalChemist on July 12, 2010 1:45 PM writes...
Why can't we just replace small molecules with monoclonals now?
Permalink to Comment20. road on July 12, 2010 1:48 PM writes...
#19
Because there are still a few important things that go on *inside* the cell.
Permalink to Comment21. newnickname on July 12, 2010 2:22 PM writes...
Also recently: Samuel Danishefsky, Nat. Prod. Rep., 2010, DOI: 10.1039/c003211p "On the potential of natural products in the discovery of pharma leads: A case for reassessment."
Basically, natural products are valuable leads and deliberately diverting synthetic intermediates (from a total synthesis) can produce greater quantities of superior candidates.
Permalink to Comment22. ronathan richardson on July 12, 2010 2:37 PM writes...
milkshake, I tried to figure out what molecule/target you were talking about in your post--could you clarify? thanks
Permalink to Comment23. milshake on July 12, 2010 3:34 PM writes...
I spoke with a neurologist here few days ago and she mentioned a lactam IV-administered cephalosporine-derived antibiotics that is in clinical trial for ALS. This antibiotics is supposed to boost levels of glutamate transporter in the brain - the one which is defective in ALS and this drives the neuronal loss. She said the drug acted as a transcription factor. I was amazed when I heard this because 1) targeting transcription is hard (but apparently this compound was discovered by screening a collection of approved drugs) 2) the stuff has to get into brain and into the nucleus
Permalink to Comment24. Drug Discoverer on July 12, 2010 3:55 PM writes...
In today's world of drug discovery, we all need as many sources of chemical leads as possible, be they natural products, existing compund banks, targeted libraries, or compounds covering new compound space. For many target classes, finding suitable chemical leads is not the problem, nor is optimizing on potency or even selectivity. The problem is having good drug properties in vivo, efficacy, safety. SS's approach does nothing toward solving these problems for us.
When people try to be too clever in providing guielines of gross generalizations, the results can often be less than helpful when applied too rigorously without context, thought, suitable judgement. Thanks Stu, again, for one of your insightful prognoses that has limited true application.
Permalink to Comment25. MedChem on July 12, 2010 4:10 PM writes...
#24
My reaction after reading the article was a lazy "so?". I really don't see the significance and brilliance that the reviewers obviously saw.
Permalink to Comment26. MoMo on July 12, 2010 4:38 PM writes...
SS always is full of good advice-NOT
How many drugs has his efforts afforded? I would think the answer is ZERO
I would like to know. In Boston we call people who dress, think and perform like him "Shreiberphiles"
Natural products will always be a good starting point for new drugs regardless of how many drugs SS and his followers produce- which I believe is near ZERO.
Permalink to Comment27. Eraser on July 12, 2010 4:54 PM writes...
MedChem
I agree.
I think Schreiber has started to belive too much in his own brilliance. Trying to cover chemical space simply by casting a net in different directions with no clear guide except "diversity" ?
Permalink to CommentGood luck
28. Phil on July 12, 2010 4:58 PM writes...
"For many target classes, finding suitable chemical leads is not the problem, nor is optimizing on potency or even selectivity. The problem is having good drug properties in vivo, efficacy, safety."
This is the part that most academics just don't understand. Activity at the picomolar level and exquisite selectivity are just the beginnings of a good drug, and even these are often sacrificed for better pharmacological behavior. These are problems that can only be solved by rational design, which is why no one should be worried about being replaced by CombiChem, DOS, or any other snake oil for drug discovery someone like Schreiber is trying to sell.
Permalink to Comment29. barry on July 12, 2010 5:28 PM writes...
re#28
Tularik spent years and tens of millions screening 2x^6 cmpds for a small-molecule inhibitor of a mammalian transcription factor and found zero. While this is rarely the hardest part of the drug discovery process, it was the killer in transcription factors. If prof. Schreiber has solved this, that's far more interesting than this paper.
Permalink to Comment30. Phil on July 12, 2010 5:41 PM writes...
re #29
TFs are specific example of what I'd argue is a very different drug target than medicinal chemists have tried to hit before, which is why it wasn't until very recently any success was found. I don't think Schreiber's DOS is going to help with that either because as Derek points out, the chemical space is practically infinite.
Chemical biology seems to have made a breakthrough in TF inhibition. http://www.the-scientist.com/blog/display/56143/
Permalink to Comment31. anonymous on July 12, 2010 6:05 PM writes...
sanofi is laying off chemists/medicinal chemists tomorrow. mgmt finds out who early morning, then meets with the doomed. site meeting tomorrow afternoon. stay tuned.
Permalink to Comment32. Anonymous on July 12, 2010 6:09 PM writes...
I'm surprised no one has mentioned Infinity. Schreiber founded Infinity several years ago, based on the claim that they could use DOS to discover revolutionary compounds against undruggable targets. Infinity raised over $100 million in VC money.
So, how did that turn out? The "DOS" part was a total failure. They found absolutely nothing. Infinity's lead clinical candidate, IPI-504, differs from the natural product geldanamycin by -- get ready -- two hydrogen atoms. Apparently when you spend $100 million on "DOS", you can figure out how to convert the quinone to the hydroquinone.
Schreiber likes to write reviews about "chemical space" and druggable proteins, but the truth is that his lab has no track record of producing useful compounds against even the most simple targets, let alone transcription factors (at least for the past 15 years, post-trapoxin). I can't think of anyone who takes Schreiber seriously at this point. Derek, why do you still post about this stuff?
Permalink to Comment33. peturbagen on July 12, 2010 7:36 PM writes...
#28 nails it. I heard Schreiber give a talk about 6 years ago where he spent half the time singing the praises about DOS then the rest of the time talking up how natural products have superior properties as drugs with no acknowledgment of the contradiction.
Isn't the problem with DOS that, to easily achieve "diversity" you need to have syntheses that work robustly in aqueous conditions? This generates libraries of molecules that are easily hydrolyzed in physiological milieus and hence would never achieve the PK profile of "drugs."
Permalink to Comment34. adrien brody on July 12, 2010 8:25 PM writes...
Derek,
I enjoy your analyses on such matters (i.e., the question of what chemical matter seems most promising). I don’t agree with some of the posts here, which seem a little overzealous about discounting the academic approach to finding interesting molecules. I don’t like the way the arguments are being built.
It seems that a recurring criterion is to ask “what drugs have you discovered”?
Really?
Isn’t that the whole point? The current strategies don’t work as well as they’re supposed to, right? Don’t we need complementary approaches that aren’t necessarily limited by the conventional wisdom of drug companies? I’m confused.
How do we find new drugs? How to we hit undruggable targets? This entire topic -- DOS, natural products, “drug-like” compounds -- it’s an open question to be sure. And it’s not clear that anyone here has the solution.
Personally, I think Schreiber is off the mark. I have a special place in my heart for NPs. But that’s another post.
Finally, a question I have for poster 32 is this: Is it fair to say DOS is a bad concept because Infinity didn’t produce a new drug lead? If they had produced a drug lead, would you feel better? (I’m guessing probably not). It’s fine if you don’t like Schreiber. Great. But I’d feel better if that wasn’t your M.O.
Permalink to Comment35. adrien brody on July 12, 2010 8:30 PM writes...
By posts I mean comments.
Permalink to Comment36. JB on July 12, 2010 8:44 PM writes...
"These are problems that can only be solved by rational design"
Permalink to CommentThere's a team of 11 medicinal chemists working at the Broad screening center (and DOS library chemists are pulled in for medchem as well):
www.broadinstitute.org/science/platforms/chemical-biology-platform/team-0
One of the design features of the DOS libraries is the ability for rapid analogging- not just at the diversity sites but within the backbone as well (see papers on the build-couple-pair strategy.)
37. Got_QSAR? on July 12, 2010 11:10 PM writes...
Natural products, DOS libraries, combichem... What ever happened to traditional medchem approaches? ANALYZE THE DATA YOU'VE ALREADY GENERATED - find trends between structure and data - make next compound. I think they use to call it rational drug design.
QSAR (2D and 3D) plus structure based design techniques is where I will put my money every time.
Permalink to Comment38. student on July 12, 2010 11:27 PM writes...
What's with all the hate for Schreiber? Does everyone want to stick with the traditional drug discovery approaches where drugs cost 1B$ to generate for all eternity? At least he's trying something new, goddamit, cut him some slack. Drug discovery is a clusterfuck of a problem, and there's no shame in not coming up with a drug in 15 years in an academic setting. Just ask Derek. Smart people are going to have to keep on trying new approaches that fail (combichem, DOS, etc), and put up with all the jeers of trying something new, if we're ever going to find something that revolutionizes the biz. Natural products are good starting points because they're usually drugs in the first place -- warfare agents, for instance, that can cross membranes and fuck shit up. But they're far from ideal, and it's not sustainable to keep on the same old path for many new druggable problems that are out there.
Permalink to Comment39. Got_QSAR on July 12, 2010 11:37 PM writes...
#38 "Does everyone want to stick with the traditional drug discovery approaches..."
IMHO that's the problem. We/they aren't sticking with the traditional approaches. In my medchem experience thus far (albeit anecdotal) I have seen more brute force approaches than rational ones being applied.
Permalink to Comment40. cliffintokyo on July 13, 2010 2:26 AM writes...
Whoah Guys:
Permalink to CommentBe certain that SS knows the patent game rules.
He needs *something* he is able to *talk* about and *some (other) thing* he is able to patent.
Academics have the *luxury* of being able to do both......
41. Anonymous on July 13, 2010 7:39 AM writes...
Adrien Brody: "Is it fair to say DOS is a bad concept because Infinity didn’t produce a new drug lead? If they had produced a drug lead, would you feel better? "
You're saying: "If the experimental result had been the opposite, would you have a different opinion?"
Yes, that's how it works.
The idea that DOS can be used to target undruggable proteins has been put to the test -- in expensive experiments at Infinity, at Schreiber's huge lab at the Broad, in the labs of his many scientific progeny. The result has been a big silence.
Sure, it was worth a try, even though the logic behind DOS is somewhat dubious, as Derek and many others have pointed out. But to claim, in 2010, that Schreiber-type DOS is going to allow us to finally target undruggable proteins! -- that is just laugh-out-loud ridiculous. Just completely disconnected from reality, when everything points to the opposite conclusion.
Permalink to Comment42. alkaloid chemist on July 13, 2010 8:20 AM writes...
I don't think Schreiber, or anyone else, is seriously anticipating DOS to pop out the next lipitor. That's not the point. The point, as #33's name implies, is to discover perturbagens of biological systems which will give us new insight into cellular mechanisms that might not have ever been discovered otherwise (robotnikinin, for example). This information is critical, and something academia is very good at (as opposed to actually making drugs). I applaud Schreiber and others for developing a rational (yes, rational) approach for discovering new and unique biological probes. Schreiber is not suggesting we stop looking to natural products to study disease biology (undoubtedly they are the best source), only that our focus may be too narrow. I guess that makes me a Schreiberphile?
Permalink to Comment43. Anonymous on July 13, 2010 8:39 AM writes...
alkaloid chemist:
poster #33 was mocking Schreiber by calling himself "perturbagen".
Permalink to Comment44. alkaloid chemist on July 13, 2010 8:45 AM writes...
#43: Thanks, but I caught that. That's why I mentioned it (sarcastically) to make a counterpoint.
Permalink to Comment45. Anonymous on July 13, 2010 9:13 AM writes...
I am starting to think that Schreiber is starting to go over the end. One of his recent talks was very confusing in its message and I thought he was trying to claim credit for some of the recent major advances in cancer and made him self out to be some sort of crusader with a I hate cancer bandana tied to his forehead. I wanted to ask him if his molecule collection could cure baldness - but then I decided no to. But its funny to see chemist lap up what he dishes out. A group of sensible biologist would hve him running for the hills.
Permalink to Comment46. iridium on July 13, 2010 1:35 PM writes...
I do not see big conceptual difference between combichem and DOS.
Could somebody comment on that?
Thank you.
Permalink to Comment47. Anonymous on July 13, 2010 2:14 PM writes...
combichem is for the synthesis of small molecules.
DOS is for the synthesis of perturbagens.
Permalink to Comment48. Hap on July 13, 2010 2:17 PM writes...
I think that combichem generally takes a common skeleton with pendant functional groups and tries to append a variety of groups on it, so there is peripheral diversity but on a common skeleton. DOS is supposed to take building blocks that are functionalizable in various ways to get different skeletons (which, depending on the functionality that can be incorporated into the building blocks, can then be functionalized peripherally as well). Basically, I think DOS is combichem in which the cores are subject to the same generation of diversity as the periphery.
I would guess it's probably hard to generate diversifiable cores reliably, because the functional handles needed to put on peripheral diversity impede the DOS sequences - so although DOS should be able to generate a greater level of diversity, it probably can't because you can't functionalize the products as well. You should get greater diversity in chemical space from a DOS library because the cores are different, but I don't know.
Permalink to Comment49. Anonymous on July 13, 2010 3:21 PM writes...
I remember reading the original Schreiber paper on DOS numerous times, trying to see just what the difference between "CombiChem" and DOS was.
Basically, all I could understand was that they were the same thing except that "CombiChem" was done by stupid people and DOS was done by smart people.
Permalink to Comment50. cynical1 on July 13, 2010 3:53 PM writes...
ronathan and milkshake - I believe the drug you are talking about for ALS is Ceftriaxone. It does have good CNS penetration. I don't know about intracellular transport.
Permalink to Comment51. Phil on July 13, 2010 3:55 PM writes...
#34 "I don’t agree with some of the posts here, which seem a little overzealous about discounting the academic approach to finding interesting molecules."
I never said academics don't find interesting molecules. The point has already been made that NPs have played a critical role in elucidating protein function, and many of the molecules discovered by DOS could serve that purpose as well.
Most of us in the chemical industry just cringe when we read a paper by someone like Schreiber that seems to suggest the next breakthrough small molecule drug is going to come from their revolutionary approach. There is a world of difference between "interesting molecule" and "drug candidate" and traversing that divide is the part that few academics understand.
Permalink to Comment52. adrien brody on July 13, 2010 4:40 PM writes...
Phil, Thanks for keeping the discussion going. Please call me Adrein.
Two things:
1. Correct me if I’m wrong: Has SLS started making claims at using DOS to discover new drugs? I thought he was going after “probes” or perturbogens. This is why I said ‘interesting molecules’, instead of drugs. I’m sure most would agree academia is not the place to do drug discovery, at least on purpose.
2. You’re the rationale design guy, right? I love rationale design. Our lab does some. But you should take yourself down a notch. Cuz there are just a few instances where a design model doesn’t behave the way it’s supposed to. And it sucks when it’s in the later stages of drug discovery. Our beloved blogger, Derek, writes about this now and again. Combichem, DOS, or whatever you want to call it, is supposed to fill in gaps in rationale design when little to nothing is known about a target. And, sometimes, this makes for good, fun, satisfying research! So relax, pleeez.
P.S. Did you see my abs in the latest Predators movie?
Permalink to Comment53. Phil on July 13, 2010 6:36 PM writes...
Adrien,
From Schreiber's 2009 JACS paper (doi: 10.1021/ja900414s)
"Small molecules are widely used for studying biology or
treating diseases. Their discovery increasingly relies on small molecule screening, although these studies have revealed the
inadequacy of screening collections based on natural products
and commercial vendor libraries. We have been exploring the
build/couple/pair strategy for the synthesis of transformative
small-molecule screening collections. These have properties that increase the probability of success in all facets of probe- and drug-discovery pipelines in which synthesis plays a role,
including discovery of initial leads, optimization of them, and
manufacturing of the optimized variant."
Sounds like a claim for DOS's transformative effect on drug discovery.
His fallacious argument is that commercial vendor libraries and NPs have failed (are inadequate). They produce hits on a regular basis. Biological activity comes cheap. Pharmacological suitability has to be worked out over several iterations.
As for your second remark, you should find a less snarky way to tell me something I already know, or I won't be keeping the discussion going for long.
Permalink to Comment54. adrien brody on July 13, 2010 8:31 PM writes...
haha, okay.
Permalink to Comment55. noname on July 16, 2010 10:32 AM writes...
I always equated DOS with "natural product-like", as did a lot of the Schreiber groupies at the latest CombiChem GRC, oops I mean High Throughput Chemical Biology GRC. So my first reaction to this paper was he was shooting himself in the foot, which I admire. But Derek's point about the Schreiberites arguing DOS occupyies the magic middle is disturbingly persuasive.
The real point is, all these theoretical arguments are attempts to address the fundamental shortcoming of our ability to explore the bioactivity of chemical space. If we could interrogate ten times the number of species for one tenth the cost, we wouldn't be making a lot of these arguments. Hmmm, I wonder if there is a technology that could do that...
Permalink to Comment56. JB on July 16, 2010 8:17 PM writes...
Are you are possibly at GSK formerly Praecis, noname?
Permalink to Comment57. ret on July 18, 2010 7:47 PM writes...
A comment which is a little late to the party but I don't think has been mentioned.
Over the last hundred years most natural products have been tested for antibiotic activity and general cytotoxicity. Our main problem is a general lack of good information on how these compounds perform in broad screens. I am sure as we increase the number of quality assays we will find natural products with broader activity.
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