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September 13, 2007
Don't Step Over It, Even If It's Right in Front of You
There are many mistakes you can make in medicinal chemistry. Hah, I got that sentence typed out with a straight face; I wasn’t sure if I could do it or not. Mistakes! We’re up to our clavicles in them. Successful R&D is the triumph of those who manage to bungle things the least, and that doesn’t go just for the drug industry. Talk to engineers, talk to software developers. You’ll get the same perspective, accompanied by much eye-rolling and waving of arms.
And getting used to this, as I’ve noted here and there, is a psychological adjustment that a working scientist has to make. Setting your standards to a no-false-starts no-blind-alleys standard guarantees your failure, or at least ensures that you’ll be driven out of the field before have time for any success. Every working chemist knows what it’s like to put a slide of reactions together for a presentation, only to realize that they’ve just summed up months of effort in what could (theoretically, ideally) have been a few day’s work.
In med-chem, I can think of many examples where I’ve worked on a project only to recommend a compound at the end that was embarrassingly close to the starting point. Twice in a row we ended up with a compound that had one methyl group added to it compared to one of the starting compounds – mind you, those methyl groups really pulled their weight. They made a big difference in the final properties of the molecule, but we’d spent a lot of time exploring bigger changes and other regions of the molecule, none of which worked out well.
Philip Larkin, a favorite poet of mine, said that he learned from Thomas Hardy's work not to be afraid of the obvious. Like a lot of good advice, though, that’s hard to take. Researchers with an optimistic bent will wander off to new parts of the lead molecule, looking for the greener grass that they’re sure is out there. And the pessimistic ones won’t do the stuff right in front of them, either, for fear of how it’ll look. Sometimes the simple stuff gets overlooked, for no other reason that it's simple. Should that count against it?
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