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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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March 29, 2010

Compounds and Proteins

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Posted by Derek

For the medicinal chemists in the audience, I wanted to strongly recommend a new paper from a group at Roche. It's a tour through the various sorts of interactions between proteins and ligands, with copious examples, and it's a very sensible look at the subject. It covers a number of topics that have been discussed here (and throughout the literature in recent years), and looks to be an excellent one-stop reference.

In fact, read the right way, it's a testament to how tricky medicinal chemistry is. Some of the topics are hydrogen bonds (and why they can be excellent keys to binding or, alternatively, of no use whatsoever), water molecules bound to proteins (and why disturbing them can account for large amounts of binding energy, or, alternatively, kill your compound's chances of ever binding at all), halogen bonds (which really do exist, although not everyone realizes that), interactions with aryl rings (some of which can be just as beneficial coming in 90 degrees to where you might imagine), and so on.

And this is just to get compounds to bind to their targets, which is the absolute first step on the road to a drug. Then you can start worrying about how to have your compounds not bind to things you don't want (many of which you probably don't even realize even are out there). And about how to get it to decent blood levels, for a decent amount of time, and into the right compartments of the body. And at that point, it's nearly time to see if it does any good for the disease you're trying to target!

Comments (5) + TrackBacks (0) | Category: Drug Assays | In Silico | Life in the Drug Labs


1. chris on March 29, 2010 1:31 PM writes...

Just finished reading the article, it is excellent and pretty comprehensive, I can see me dipping into it regularly.

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2. mad on March 29, 2010 4:18 PM writes...

Good one

Thanks for posting the link

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3. retread on March 29, 2010 9:19 PM writes...

All very nice, if proteins are the only drug targets there are. But they aren't. It appears that over 50% (and perhaps nearly 100%) of our genome is transcribed into RNA. Nature uses small molecules to interact with RNAs to control their activity. Why shouldn't you? (Google riboswitches). I may do a post on them in the future, but life appears to be interrupting blogging.

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4. Handles on March 30, 2010 1:17 AM writes...

And its Open Access too. Nice one, Roche.

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5. partial agonist on March 30, 2010 9:17 AM writes...

Very nice paper with just enough real examples to hold your attention- THANKS DEREK!

Particularly interesting is all of the structural info/requirements about weak interactions not requiring significant desolvation penalties. Still a mystery is how to logically seek out potential weak interactions to exploit. Some of the minor points are mildly surprising, like how sulfonyl oxygens are as likely to participate in solid hydrophobic interactions as they are to H-hond, that ethers can be pathetic acceptors, the always fascinating halogen-bonding phenomena, and of course the fact that hydrophobic packing rules (in binding).

Now if there wasn't all of that DMPK/solubility/permeability stuff to worry about, the crystallographers could discover lots of good drugs. As it is, they discover lots of good binders! Never forget, almost all the major issues come back to the bench chemists to solve.

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