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September 29, 2005
The Hazards of Molecular Modeling
A comment to the last post really gave me the shivers:
"I like to think of modelling as the "silent killer". It is easy to rely on it for quick answers, and easy to forget that there is no substitute for an actual experiment. . .
I remember asking a fellow scientist if a particular molecule performed as hypothesized, the response was: " I don't know. It did not dock well into the enzyme, so I didn't make it."
I've made this point before, but it needs to be made again: molecular modeling is not reality. Most models are not that good, or only good around a limited group of rather similar compounds. If you as a medicinal chemist are crossing out easy-to-make compounds in unexplored chemical space just because the software doesn't like it, you are handcuffing yourself and tying your thumbs together. Stop it, stop it for your own good, or you may never discover anything unexpected or useful.
"The silent killer": I like that phrase a lot. I get the occasional testy e-mail from the computational types when I talk like this, but I'm sticking to my beliefs here. Molecular models based on numerous high-resolution X-ray structures are, I think, sort of useful, sometimes. Models based on only one X-ray structure are to be approached with great caution. And binding models that are just calculated up de novo should be treated as hazardous to your scientific health, unless you have a great deal of evidence to make you think otherwise.
OK, you silicon jockeys, go ahead and flood my in-box. I've earned it.
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