I've started my Memorial Day weekend early (thus the mid-morning posting time.)

One of the comments to the previous post mentions the "let's make these compounds because we can" attitude, and points out that this was the fallacy underlying the combichem boom (and bust.) True enough - I should have clarified my point by saying that the compounds I was recommending were much more targeted. They're related to a structural series that we know we're interested in, but we haven't made tested anything from this particular group yet.

And, truth be told, I don't mind the blue-sky let's-make-some-compounds approach, as long as it's done in moderation. Throwing some interesting structures into the screening files is never a waste of time, although there are often more pressing things to do.

I don't approve of sending in things that are poor candidates for starting off an optimization project, though. If something with a molecular weight of 1300 hits in your assay, there's often not much you can do about it. That's at least twice a reasonable molecular weight, and large compounds like that often can't be cut down to size. Their binding modes are complex, interesting, and almost impossible to deal with in any practical manner, unfortunately. Getting a handle on things like this is a longstanding problem in drug discovery, so unless you feel like solving it, you shouldn't add to it.

Similarly, anyone who sends in reactive compounds like acid chlorides deserves a whack over the head. Those things, assuming they don't fall apart in storage, will tear up most assays they're run in, and it's not like they're ever going to be drugs. Same goes for things like organotelluriums and other out-there elements. I have a fairly liberal attitude (silicon-carbon bonds are OK with me), but there's a limit. If you think someone's going to be happy when your nickel complex hits in their enzyme assay, you are not in touch with consensus reality.

The problem with the combichem boom wasn't always the underlying compounds, although some of them were stinkers (and most of them sure could have been cleaner.) I think the real trouble was how oversold the whole thing became. If you weren't buying or cranking out huge libraries, you were missing the gold rush. Vast untapped veins of drug leads were out there in those hills! Without the hype, things wouldn't have looked so bad. But hey, without the hype, most of those libraries wouldn't have been made. . .