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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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 23, 2013

Eating A Whole Bunch of Random Compounds

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Posted by Derek

Reader Andy Breuninger, from completely outside the biopharma business, sends along what I think is an interesting question, and one that bears on a number of issues:

A question has been bugging me that I hope you might answer.

My understanding is that a lot of your work comes down to taking a seed molecule and exploring a range of derived molecules using various metrics and tests to estimate how likely they are to be useful drugs.

My question is this: if you took a normal seed molecule and a standard set of modifications, generated a set of derived molecules at random, and ate a reasonable dose of each, what would happen? Would 99% be horribly toxic? Would 99% have no effect? Would their effects be roughly the same or would one give you the hives, another nausea, and a third make your big toe hurt?

His impression of drug discovery is pretty accurate. It very often is just that: taking one or more lead compounds and running variations on them, trying to optimize potency, specificity, blood levels/absorption/clearance, toxicology, and so on. So, what do most of these compounds do in vivo?

My first thought is "Depends on where you start". There are several issues: (1) We tend to have a defined target in mind when we pick a lead compound, or (if it's a phenotypic assay that got us there), we have a defined activity that we've already seen. So things are biased right from the start; we're already looking at a higher chance of biological activity than you'd have by randomly picking something out of a catalog or drawing something on a board.

And the sort of target can make a big difference. There are an awful lot of kinase enzymes, for example, and compounds tend to cross-react with them, at least in the nearby families, unless you take a lot of care to keep that from happening. Compounds for the G-protein coupled biogenic amines receptors tend to do that, too. On the other hand, you have enzymes like the cytochromes and binding sites like the aryl hydrocarbon receptor - these things are evolved to recognize all sorts of structually disparate stuff. So against the right (or wrong!) sort of targets, you could expect to see a wide range of potential side activities, even before hitting the random ones.

(2) Some structural classes have a lot more biological activity than others. A lot of small-molecule drugs, for example, have some sort of basic amine in them. That's an important recognition element for naturally occurring substances, and we've found similar patterns in our own compounds. So something without nitrogens at all, I'd say, has a lower chance of being active in a living organism. (Barry Sharpless seems to agree with this). That's not to say that there aren't plenty of CHO compounds that can do you harm, just that there are proportionally more CHON ones that can.

Past that rough distinction, there are pharmacophores that tend to hit a lot, sometimes to the point that they're better avoided. Others are just the starting points for a lot of interesting and active compounds - piperazines and imidazoles are two cores that come to mind. I'd be willing to bet that a thousand random piperazines would hit more things than a thousand random morpholines (other things being roughly equal, like molecular weight and polarity), and either of them would hit a lot more than a thousand random cyclohexanes.

(3) Properties can make a big difference. The Lipinski Rule-of-Five criteria come in for a lot of bashing around here, but if I were forced to eat a thousand random compounds that fit those cutoffs, versus having the option to eat a thousand random ones that didn't, I sure know which ones I'd dig my spoon into.

And finally, (4): the dose makes the poison. If you go up enough in dose, it's safe to say that you're going to see an in vivo response to almost anything, including plenty of stuff at the supermarket. Similarly, I could almost certainly eat a microgram of any compound we have in our company's files with no ill effect, although I am not motivated to put that idea to the test. Same goes for the time that you're exposed. A lot of compounds are tolerated for single-dose tox but fail at two weeks. Compounds that make it through two weeks don't always make it to six months, and so on.

How closely you look makes the poison, too. We find that out all the time when we do animal studies - a compound that seems to cause no overt effects might be seen, on necropsy, to have affected some internal organs. And one that doesn't seem to have any visible signs on the tissues can still show effects in a full histopathology workup. The same goes for blood work and other analyses; the more you look, the more you'll see. If you get down to gene-chip analysis, looking at expression levels of thousands of proteins, then you'd find that most things at the supermarket would light up. Broccoli, horseradish, grapefruit, garlic and any number of other things would kick a full expression-profiling assay all over the place.

So, back to the question at hand. My thinking is that if you took a typical lead compound and dosed it at a reasonable level, along with a large set of analogs, then you'd probably find that if any of them had overt effects, they would probably have a similar profile (for good or bad) to whatever the most active compound was, just less of it. The others wouldn't be as potent at the target, or wouldn't reach the same blood levels. The chances of finding some noticeable but completely different activity would be lower, but very definitely non-zero, and would be wildly variable depending on the compound class. These effects might well cluster into the usual sorts of reactions that the body has to foreign substances - nausea, dizziness, headache, and the like. Overall, odds are that most of the compounds wouldn't show much, not being potent enough at any given target, or getting high enough blood levels to show something, but that's also highly variable. And if you looked closely enough, you'd probably find that that all did something, at some level.

Just in my own experience, I've seen one compound out of a series of dopamine receptor ligands suddenly turn up as a vasodilator, noticeable because of the "Rudolph the Red-Nosed Rodent" effect (red ears and tail, too). I've also seen compound series where they started crossing the blood-brain barrier more more effectively at some point, which led to a sharp demarcation in the tolerability studies. And I've seen many cases, when we've started looking at broader counterscreens, where the change of one particular functional group completely knocked a compound out of (or into) activity in some side assay. So you can never be sure. . .

Comments (22) + TrackBacks (0) | Category: Drug Assays | Drug Development | Pharma 101 | Pharmacokinetics | Toxicology


COMMENTS

1. LeeH on January 23, 2013 12:29 PM writes...

There seem to be two parts to the question.

First, given molecules that are within a certain chemical distance from the starting molecule, what is the probability that it has similar activity? This is the so-called similarity principle, and has been studied at some length. Under the hood, it's the principle behind much of computational chemistry as it's practiced in industry. And the answer is, yes, there's a much higher than random chance that the similars share the same activity as the starting point.

The other question is the converse, that is, what is the probability that the similars have different activities? That's much harder to answer, but it's probably about the same probability that the original compound had other activities, known or otherwise.

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2. neo on January 23, 2013 12:29 PM writes...

A pleasant drought of methanol/ethanol/ethylene glycol/propylene glycol should be instructive. Briefly.

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3. LeeH on January 23, 2013 12:33 PM writes...

Another point.

Properties can fall off smoothly with increasing chemical distance, others much more quickly (now referred to as activity cliffs). Practically speaking, you hope that the desirable properties fall off smoothly, while the undesirable ones change quickly. Unfortunately things don't go exactly the way you want most of the time.

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4. Pete on January 23, 2013 12:50 PM writes...

We typically quantify molecular similarity using molecular fingerprints and the size of the effect of a structural modification (e.g. hydrogen to chlorine; aromatic CH to N; amide 'reversal' will usually depend on the nature of the 'reference' structure. In fingerprint terms, a given strucutural modification will usually appear to have a smaller effect as the reference structure becomes more complex.

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5. RKN on January 23, 2013 1:47 PM writes...

If you get down to gene-chip analysis, looking at expression levels of thousands of proteins, then you'd find that most things at the supermarket would light up. Broccoli, horseradish, grapefruit, garlic and any number of other things would kick a full expression-profiling assay all over the place.

That's quite sobering. I frequently work with genome-wide expression data (gxpr). Lately, we've been working with several gxpr data sets from patients in two groups, responders & non-responders, using samples obtained before and 12 hours after taking a particular drug.

It didn't occur to me that any significant difference in gene expression between the two patient groups before seeing the drug may be colored by what they ate the night before.

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6. Derek Lowe on January 23, 2013 2:00 PM writes...

#5 RKN:

You might only see the effects in the gut tissue, but who knows? Grapefruit has well-known effects on the expression of the intestinal CYP isoforms, for one thing. And here's a reference on garlic, in a cell assay, at least: http://www.tandfonline.com/doi/abs/10.1207/S15327914NC382_15.

Here are some broccoli/brassica references: http://www.ncbi.nlm.nih.gov/pubmed/22640941
http://www.ncbi.nlm.nih.gov/pubmed/22303412
http://www.ncbi.nlm.nih.gov/pubmed/18781917


As for horseradish, it's a tough literature search, because you have to clear out all the "horseradish peroxidase". But the active ingredient is allyl isothiocyanate, and that has been looked at in cell lines: http://www.ncbi.nlm.nih.gov/pubmed/18997101

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7. RM on January 23, 2013 2:35 PM writes...

RKN@5 - It didn't occur to me that any significant difference in gene expression between the two patient groups before seeing the drug may be colored by what they ate the night before.

The hope would be that your sample size and randomization would be enough to smooth over any difference. (The chance that all of the responders had broccoli last night for dinner while none of the non-responders did is hopefully low - as long as broccoli consumption isn't what's causing the difference, and you didn't happen to solicit one population from the Broccoli-Eaters Association of America or from a single family that eats dinner together.)

Human trials are complicated by a host of things besides diet. Amount of sleep, differences in physical activity, genetics, hormone levels (were your patients "amorous" last night?), etc. You could ask for genetically identical humans fed a uniform diet in controlled lab conditions, but IRBs tend to frown upon that for some reason. "Large" sample sizes and good randomization is typically the best you can do.

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8. Peter Ellis on January 23, 2013 3:30 PM writes...

What did you do with your red-nosed rodent compound? Drop it, or follow up? Is there any scope for pursuing these kind of unexpected leads to see if you end up with a drug for something other than the originally-intended purpose?

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9. Anon on January 23, 2013 3:34 PM writes...

When I was starting graduate school, a soon to be graduating MS received an interview to Scripps for their Ph.D. program and came back with a crazy tale about his meeting with a very well known chemist there; apparently one of his graduate students came into his office during the interview with 10mcg of final product and said chemist put it in his hand and licked it, looked at his graduate student and said it tasted kind of funny and he should repeat the final step. Now, I have know idea if this is true but my source would have no reason to lie. Our PI, upon hearing this, said that he was trying things out to see if he would get high. I personally thought it was a funny story and this piece reminded me of it. I guess you could ask this chemist about this peculiar habit and what he's personally learned about derivatives.

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10. RKN on January 23, 2013 7:51 PM writes...

@Derek,

Fascinating. Thank you for the links.

@RM,

It occurred to me after I commented that patients would have likely been asked to fast the night before having a sample taken.

As for cohort size, we rarely have as many samples as we'd like, but we do the best we can.

Permalink to Comment

11. Eric Jablow on January 23, 2013 8:10 PM writes...

If you're really unlucky, you immediately develop incurable Parkinson's Disease.

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12. Anonymous on January 24, 2013 1:34 AM writes...

The questioner might be interested in reading the chemistry section of PIHKAL or TIHKAL; there's around 175 compounds, most of which are variations on phenethylamines, and discussions of the effects as caused by varying doses.

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13. xfin31 on January 24, 2013 3:05 AM writes...

Strangely, this is actually being done, right now, in labs designed to make the next set of designer drugs. I can't trace back the article now, but it was an interview with a guy running a european backstreet lab in which they take a psychoactive starting point and make point changes to come up with a analog with comparable effects, but outside the scope of the legal ban. Then, some lucky volunteer gets to test the analogue.

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14. xfin31 on January 24, 2013 3:06 AM writes...

Strangely, this is actually being done, right now, in labs designed to make the next set of designer drugs. I can't trace back the article now, but it was an interview with a guy running a european backstreet lab in which they take a psychoactive starting point and make point changes to come up with a analog with comparable effects, but outside the scope of the legal ban. Then, some lucky volunteer gets to test the analogue.

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15. as2o3 on January 24, 2013 4:20 AM writes...

#14: It may have been an interview with the guy who "designed" methoxetamine, it's posted on Vice.com

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16. TX Raven on January 24, 2013 6:01 AM writes...

@3, LeeH

"Unfortunately things don't go exactly the way you want most of the time."

Amen to that.
IMHO, the perceived lower cost of computational calculations compared with in vitro screens has made folks believe that biological activity is a "linear" property.

As they say back home, you get what you pay for...

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17. oldtimer on January 24, 2013 9:24 AM writes...

Of course, at the beginning of standardized organic chemistry not only was the color, size, shape and melting point of the crystals of a new compound recorded, but also the taste.

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18. xfin31 on January 24, 2013 11:02 AM writes...

I posted the link, but it's held in moderation at the moment.

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19. xfin31 on January 24, 2013 11:06 AM writes...

Sumatriptan has a really bitter taste, I know that at least one marketed follow up triptans was tasted by the lead pharmacologist on the project very early on to see whether taste could be a differentiating factor.

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20. Doug Steinman on January 24, 2013 1:53 PM writes...

Read the history of the discovery of Aspartame at Searle. The sweetness of the molecule was discovered by the investigator and his boss tasting it. Sorry, I don't have a link but it should be easy to find.

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21. xfin31 on January 25, 2013 8:59 AM writes...

Here's a quote from the article in the WSJ ... "Mr. Llewellyn, meanwhile, is unfazed. He boasts that his safety testing method is foolproof: He and several colleagues sit in a room and take a new product "almost to overdose levels" to see what happens. "We'll all sit with a pen and a pad, some good music on, and one person who's straight who's watching everything," he says.". http://online.wsj.com/article/SB10001424052748704763904575550200845267526.html

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22. exGlaxoid on January 25, 2013 11:21 AM writes...

I have heard many stories of old time chemists tasting their products as part of their characterization. As well, I have heard of several scientists doing self-experimentation, even in legitimate companies and universities, much less clandestine labs.

As well, I have noticed that some artificial sweeteners do create a sweet taste in the air, just from their dust fumes. So it is certainly possible to ingest small amounts of compounds by accident, which has been seen with potent opiates as well. If you look back 50+ years, drug discovery groups used to commonly do experiments in humans often, many times on themselves or other volunteers, with little regulation. One of the first tests of penicillin was with a crude material that had barely been tested at all, much less in animals. ( http://www.psr.org/chapters/oregon/first-use-of-penicillin.html )

I do believe that did create a more productive effort and wish that we could combine our wealth of new knowledge with a better way to do small trials in a timely manner, which I think could create a huge new number of useful drugs. The combination of clinical regulations, liability concerns, and over-reliance on in-vitro or in-silico tests has all but killed drug discovery in the US. I would not be surprised to see more scientists go back to testing themselves when they find ideas for diseases that they or loved ones have but cannot get permission to test them. If I had cancer or some horrible illness, I would certainly be willing to try.

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