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

« EMBL Chemical Biology: Substrate Activity Screening | Main | EMBL Chemical Biology: The ChEMBL Database »

September 28, 2012

EMBL Chemical Biology: Polypharmacology

Email This Entry

Posted by Derek

Brian Shoichet is talking about the old days, 1930 to about 1985 or so. He mentions that Sir James Black called it "rational drug design" back then, which must have been a reaction to something that was considered really irrational. But these guys had a lot of advantages, which is what's leading people back to phenotypic screening. (I can see that I'll need to adjust my own presentation later today, because I'm going to be making the same point!)

His talk is mostly on this recent work, which I'll be blogging about separately soon, because there's a lot of drug discovery information in there. He's wondering as well about why polypharmacology is so pervasive - his studies are pointing that out in detail, but relating that to the old-style of drug discovery suggests that this isn't always a bug, but a feature. Hard-core target-based drug discovery is taking a bit a beating around here today, I have to say.

He's also made a very interesting point which looks to be the subject of an upcoming paper: that living systems signal in a number of time domains, and that this is reflected in ligands. You can see cases (like serotonin) where evolution has used the same ligand in a short time-domain case (ion channels) and a longer one (GPCRs). Nuclear receptors and some other classes work on even longer time scales. Some polypharmacology comes from across-time-domain effects.

Comments (6) + TrackBacks (0) | Category:


COMMENTS

1. Pete on September 28, 2012 7:09 AM writes...

It's actually very difficult to prove that polypharmacology is actually 'happening' (i.e. that the beneficial effect of a drug actually due to it engaging more than one target). For extracellular targets we know the drug's free concentration (and its time dependence). Everything gets a lot more complicated When the target is intracellular, on the far side of the BBB or when the targets are in different compartments.

Permalink to Comment

2. A. Skeptic on September 28, 2012 9:17 AM writes...

I'd love to see a citation, or any proof at all, about the time domains thing.

Permalink to Comment

3. simpl on September 28, 2012 10:11 AM writes...

@ pete: Do subtypes of receptors count? They are often affected to diffeing extents by a particular drug. Also, what about related receptors presumed to have evolved to allow differential responses?

Permalink to Comment

4. Imaging guy on September 28, 2012 12:02 PM writes...

Endogenous small molecule such as acetylcholine binds to muscarinic (GPCR) and nicotinic (ion channels) receptors. Their protein structures are completely different. You do not have to use time domains to explain polpharmacology of small molecules.

Permalink to Comment

5. NoDrugsNoJobs on September 28, 2012 4:05 PM writes...

#2 - Time domain signaling through different pathways is a clear feature of nuclear receptor signaling. Nuclear receptor not only leads to gene transcription via ligand-cofactor-DNA interactions but the liganded nuclear receptors also can signal via very fast phosphorylation events thereby influencing different pathways occuring on very different time scales. This is the so called and genomic and non-genomic signaling pathways for which I recall their being tons of evidence. Here is a link for a paper on ER signaling. There are thosands in toto, I think.

http://mend.endojournals.org/content/19/4/833.full

Permalink to Comment

6. Trulla on September 29, 2012 11:02 AM writes...

Polypharmacology/time domain signalling is another example of why Medicinal Chemists should buddy up more with their DMPK colleagues.
In vivo exposure is as much about location and duration as it is about concentration!

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
Adoptive T-Cell Therapy for Cancer: The Short Version
How Much Is Wrong?
The 2013 Drug Approvals: Not So Great?
Positive Rules and Negative Ones
Prices Rising - Every Year, Every Drug?
Easy Aziridines
Back Blogging (Bonus Biographical Begging)
It Just So Happens That I Have A Conference Right Here