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March 29, 2010
Compounds and Proteins
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)
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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.
Permalink to Comment2. mad on March 29, 2010 4:18 PM writes...
Good one
Thanks for posting the link
Permalink to Comment3. 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.
Permalink to Comment4. Handles on March 30, 2010 1:17 AM writes...
And its Open Access too. Nice one, Roche.
Permalink to Comment5. 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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