We left you rather abruptly in the previous post, having been stung by your suggestion that we might be uncouth. However, we have decided to forgive you and continue with our tale.
We'll start with a scenario with which many of our loyal and patient readers will be familiar. You're optimising a series and have found that adding a chloro substituent at C4 of one of the phenyl rings increases the pIC50 (-log IC50 in concentration units of mol/litre) by a unit regardless of what substituents are present at C3 and C5. Those of you who've worked in drug discovery will have seen this sort of thing. Everybody in the project knows that the 4-chloro substituent is good for potency and if it goes the potency has to be clawed back from somewhere else. Just like tax.
This sort of thinking is the basis of Free-Wilson analysis. The C4 chlorine and the hydrogen of the unsubstituted C4 can each be thought of as contributing to potency. The contribution of the chlorine is a log unit greater than that of hydrogen. So you've recognised this pattern in your project data but this isn't good enough. What do you mean, "not good enough". You have quite some nerve, M. le Crapshoot. Nothing to do with us. The Chemistry Discipline Review Committee have decided that they'd really prefer that you did this sort of thing with some equations rather than this uncultured chemical structure stuff. Also Senior Pharma Fellow (SPF) needs some equations for the presentation slides that his secretary is preparing for him. Can't you just generate some predictive models instead of being so difficult.
Well you didn't handle that very well, did you? Anyway stop complaining because you've got work to do. You do some modelling and you find out the Hammett sigmas (both meta and para) for the C4 substituent are both useful predictors of pIC50 as are the substituent hydrophobicity parameter and the molar mass of the substituent. Then you make a startling discovery.
The molecules with which you're building the models either have chlorine at C4 or are unsubstituted at this position.
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4 comments:
Well, your point is absolutely right. However, you will never really achieve a sufficient sampling of chemical space to escape from that bottleneck.
In your C4-example you are actually in a rather lucky position - because you have two variations at that position. How many positions in your molecule were never varied because they are "synthetically inaccessible"?
This is an entirely hypothetical molecule that I'm using to illustrate the discrete nature of a chemical space defined by subsituent variation. Inadequate coverage of chemical space resulting from poor synthetic accessibility is a real issue but not the one that I'm addressing here. The next post will hopefully clarify things.
Is this the same theory as Topliss diagrams?
It was extremely interesting for me to read the article. Thank author for it. I like such themes and anything connected to this matter. I definitely want to read a bit more soon.
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