1. 3D fragments are real and very useful. However, fSP3 is a horrible way to measure 3D-arity. Principal Moment of Inertia (PMI) is a much better way to determine this. This was mentioned in a brilliant talk (watered down from full-fledged rant) by me. But much better explained by Justin Bower of the Beatson Institute.
2. Solubility, Solubility, and Solubility. Experimentally determined solubility is a much better indicator of fragment quality (for a library) than cLogP, for example.
3. The Voldemort Rule (or the rule that shall not be named). Arbitrary "rules" created as a marketing tool have no place in a discipline that has over a decade of results and empirical evidence. While Dan is not ready to put a stake in its heart, I am. Rod Hubbard is. Who else wants to join Zartler-Dore's Army?
I think that van der Waals would have been most amused to see the lather that drug discovery scientists have worked themselves into over '3D-ness'. All real molecules have volume and you can't have volume with only 2 dimensions. Perhaps people need to start talking about molecular shape?
ReplyDeleteHi Pete, what a PMI plot shows is just whether a fragment can access regions that are away from the flat left side of the plot. We are not really looking at a final shape space. 3D-ness may be not "technically" exact but (intuitively)acceptable when talking about ratios of depth/width/height for the molecular boundary box.
ReplyDeleteI think of cLogP as:
ReplyDelete"Aqueous solubility is high enough to actually do the assays, check. cLogP is high enough that it must actually also be soluble in fat, check."
Because that's what we really want, right? We want a molecule that is both quite soluble in water and membrane. We just don't have any models that predict solubility well.
In my opinion In3D property is important but, soft scaffold property (able to direct derivatisation might be even more important. +D compounds are rarely insoluble.
ReplyDelete