Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Lab Animals Wiped Out in Hurricane Sandy | Main | Caring About Yields? »

November 2, 2012

Sudden Onset of Promiscuity

Email This Entry

Posted by Derek

That title should bring in the hits. But don't get your hopes up! This is medicinal chemistry, after all.

"Can't you just put the group in your molecule that does such-and-such?" Medicinal chemists sometimes hear variations of that question from people outside of chemistry - hopeful sorts who believe that we might have some effective and instantly applicable techniques for fixing selectivity, brain penetration, toxicity, and all those other properties we're always trying to align.

Mostly, though, we just have general guidelines - not so big, not so greasy (maybe not so polar, either, depending on what you're after), and avoid a few of the weirder functional groups. After that, it's art and science and hard work. A recent J. Med. Chem. paper illustrates just that point - the authors are looking at the phenomenon of molecular promiscuity. That shows up sometimes when one compound is reasonably selective, but a seemingly closely related one hits several other targets. Is there any way to predict this sort of thing?

"Probably not", is the answer. The authors looked at a range of matched molecular pairs (MMPs), structures that were mostly identical but varied only in one region. Their data set is list of compounds in this paper from the Broad Institute, which I blogged about here. There are over 15,000 compounds from three sources - vendors, natural product collections, and Schreiber-style diversity-oriented synthesis. The MMPs are things like chloro-for-methoxy on an aryl ring, or thiophene-for-pyridyl with other substituents the same. That is, they're just the sort of combinations that show up when medicinal chemists work out a series of analogs.

The Broad data set yielded 30954 matched pairs, involving over 8000 compounds and over seven thousand different transformations. Comparing these compounds and their reported selectivity over 100 different targets (also in the original paper), showed that most of these behaved "normally" - over half of them were active against the same targets that their partners were active against. But at the other end of the scale, 829 compounds showed different activity over at least ten targets, and 126 of those compounds different in activity by fifty targets or more. 33 of them differed by over ninety targets! So there really are some sudden changes out there waiting to be tripped over; they're not frequent, but they're dramatic.

How about correlations between these "promiscuity cliff" compounds and physical properties, such as molecular weight, logP, donor/acceptor count, and so on? I'd have guessed that a change to higher logP would have accompanied this sort of thing over a broad data set, but the matched pairs don't really show that (nor a shift in molecular weight). On the other hand, most of the highly promiscuous compounds are in the high cLogP range, which is reassuring from the standpoint of Received Med-Chem Wisdom. There are still plenty of selective high-logP compounds, but the ones that hit dozens of targets are almost invariably logP > 6.

Structurally, though, no particular substructure (or transformation of substructures) was found to be associated with sudden onset of promiscuity, so to this approximation, there's no actionable "avoid sticking this thing on" rule to be drawn. (Note that this does not, to me at least, say that there are no such things are frequent-hitting structures - we're talking about changes within some larger structure, not the hits you'd get when screening 500 small rhodanine phenols or the like). In fact, I don't think the Broad data set even included many functional groups of that sort to start with.

The take-home:

On the basis of the data available to us, it is not possible to conclude with certainty to what extent highly promiscuous compounds engage in specific and/or nonspecific interactions with targets. It is of course unlikely that a compound might form specific interactions with 90 or more diverse targets, even if the interactions were clearly detectable under the given experimental conditions. . .

. . .it has remained largely unclear from a medicinal chemistry perspective thus far whether certain molecular frameworks carry an intrinsic likelihood of promiscuity and/or might have frequent hitter character. After all, promiscuity is determined for compounds, not their frameworks. Importantly, the findings presented herein do not promote a framework-centric view of promiscuity. Thus, for the evaluation and prioritization of compound series for medicinal chemistry, frameworks should not primarily be considered as an intrinsic source of promiscuity and potential lack of compound specificity. Rather, we demonstrate that small chemical modifications can trigger large-magnitude promiscuity effects. Importantly, these effects depend on the specific structural environment in which these modifications occur. On the basis of our analysis, substitutions that induce promiscuity in any structural environment were not identified. Thus, in medicinal chemistry, it is important to evaluate promiscuity for individual compounds in series that are preferred from an SAR perspective; observed specificity of certain analogs within a series does not guarantee that others are not highly promiscuous."

Point taken. I continue to think, though, that some structures should trigger those evaluations with more urgency than others, although it's important never to take anything for granted with molecules you really care about.

Comments (10) + TrackBacks (0) | Category: Chemical News | Drug Assays | Natural Products | Toxicology


COMMENTS

1. MLBpitcher and Medicinal Chemist on November 2, 2012 11:26 AM writes...

I thought MMP meant "matrix metalloproteinase" but I am only a baseball fan, not an MLB pitcher who also moonlights as a medicinal chemist.

Permalink to Comment

2. Christophe Verlinde on November 2, 2012 12:28 PM writes...

It would be wise to subject these samples of "super promiscuous" compounds to NMR and MS analysis.
Many bewildering properties of particular compounds may turn out to be due to reactive contaminants.
Just ask any HTS expert worth their spit.

Permalink to Comment

3. TX raven on November 2, 2012 1:05 PM writes...

@2: goid point...
I'd be curious... Are the compounds homochiral?

Permalink to Comment

4. Imaging guy on November 2, 2012 1:52 PM writes...

In the first paragraph of that paper,I find these two terms. "nonspecific binding events" and "specific interactions of compounds with multiple (related or unrelated)targets". How do they differ chemically?

Permalink to Comment

5. MoMo on November 2, 2012 3:00 PM writes...

#4 Imaging guy-- How do they differ? Concentrations. At high concetrations molecules can have non-specific binding while at low concentrations some molecules can have specific interactions with multiple targets and unrelated to chemical factors such as VDW based lipophilicity.

Cool subject and timely.

Permalink to Comment

6. ronathan richardson on November 2, 2012 3:20 PM writes...

Based on their graphical abstract, I'm surprised that oxyanion has no effect on the promiscuity

Permalink to Comment

7. TX raven on November 2, 2012 4:35 PM writes...

@5: Not sure I agree with your definition.
For example, the binding of drugs to plasma proteins tends to happen with lower affinities than at their pharmacological targets, and yet is tends to be specific and occur in well characterized binding sites in albumin or AAG, depending on the drug's structure...

Permalink to Comment

8. exchemist on November 3, 2012 4:45 AM writes...

@5,@7: As far as I know, "nonspecific" = "non-stoichiometric". Non-specific binding might be to the target protein or to something else in the assay system e.g. detection antibody or plastic plate, as long as it gives rist to measured activity.

Permalink to Comment

9. PTM on November 3, 2012 6:19 AM writes...

My guess would be that such sudden onsets have to do with binding to common (and therefore biologically important) protein motifs. If the change makes your molecule fit (removes steric hindrance or allows it to make critical H-bonds, etc) some common protein motif it should suddenly become promiscuous.

Permalink to Comment

10. biologyisajoke on November 5, 2012 7:07 AM writes...

The assays are too fuzzy, that's all there is too it

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
How Not to Do It: NMR Magnets
Allergan Escapes Valeant
Vytorin Actually Works
Fatalities at DuPont
The New York TImes on Drug Discovery
How Are Things at Princeton?
Phage-Derived Catalysts
Our Most Snorted-At Papers This Month. . .