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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: Weird Aggregating Compounds | Main | EMBL Chemical BIology: Natural Product Multiheterocycles »

September 26, 2012

EMBL Chemical Biology: Covalent Probes

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Posted by Derek

A short talk from Steven Verhelst of Munich went into detail on some covalent probes for rhomboid proteases. I've been interested for a while about what happens when you run small electrophilic compounds over proteins - do they stick to everything, or can they show selectivity? The canonical paper on this topic is from the Cravatt group, which I'd recommend to anyone who finds this topic worthy. (Update: the Liebler group at Vanderbilt has also published some excellent work in this area, concentrating on Cys modification). Verhelst had one variety of electrophile that was selective in the active site, and another class that inhibited by sticking all over the place. So the answer is probably "Depends on your protein, and on your electrophile. Try it and see".

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


1. Sam on September 26, 2012 11:36 AM writes...

Sure, the Cravatt paper was great, but an earlier paper by Dan Liebler addresses some of these issues too - Chem. Res. Toxicol. 2008,21,2361.

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2. barry on September 26, 2012 11:48 AM writes...

In the context of drug discovery, we usually want to break out the covalent binders in reversible and irreversible. Peptide nitriles form covalent thioimidates reversibly in cysteine-protease active sites. Likewise peptide aldehydes and alpha-keto-amides form reversible covalent tetrahedral adducts in serine proteases. These seem less worrisome than irreversible covalent adducts formed from e.g. iodoacetamide.
Of course, if the off-rate of a reversible binder is comparable to the working life of the target protein, the question may be moot.

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3. Imaging guy on September 26, 2012 1:29 PM writes...

According to Dan Liebler (if I understand correctly) covlanet binding is dangerous. Others say it is not necessarily so. E.g. "The resurgence of covalent drugs" in "NATURE REVIEWS DRUG DISCOVERY, 2011". Your opinions?

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4. anonymous on September 26, 2012 7:29 PM writes...

Based on personal (scientific) experience, I think selective (key word) irreversible inhibitors make GREAT proof of concept molecules

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5. Ramesh Sistla on September 27, 2012 1:20 AM writes...

May be both reversible and irreversible inhibitors should be characterized by their residence times. An irreversible inhibitor could be treated like a reversible one with a longer residence time. There are examples of irreversible inhibitors which 'fall off' faster than a reversible inhibitor. While it is a good idea from a mechanism perspective to know whether a certain inhibitor forms an adduct or not, from a drug discovery point of view we could do well to characterize the residence times (may not easy to do in all cases though).

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6. RJH on September 30, 2012 9:15 AM writes...

Before getting too worked up about whether or not covalent binders are worthwhile avenues to develop, note that Derek's tagline mentions this work as covalent PROBES. Probe compounds aren't always meant to be drugs (i.e. ADME PK characteristics to go forward to market), just selective molecules used to tease out biological target mechanistic information and the like.

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