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

September 28, 2012

EMBL Chemical Biology: Polypharmacology

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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:


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.

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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.

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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?

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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.

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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.

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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!

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