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Free Wilson Analysis

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How often have you been in this situation?  You're working on a drug discovery project, you're in mid to late lead optimization, and you're wondering "what have we missed".  "Are there promising combinations of substituents that we didn't synthesize"? Wouldn't it be great if you could look at all the substituent combinations that you didn't make, and identify the combinations that appear promising?

Wow, you ask, what is this snazzy new technique?  Actually, it's not a new technique, it's Free-Wilson analysis, which was originally published in 1964.  The method is pretty simple and can be illustrated through an example like the one in a 1998 review by Hugo Kubinyi.  In this blog post, I'll walk through the method using a Python implementation in GitHub.  

1. R-group Decomposition
Let's assume we have a set of molecules built around this Markush structure


In addition, let's assume that we have this set of molecules that vary …