Predicting What Group to Put On Next

Here's a new paper in J. Med. Chem. on software that tries to implement matched-molecular-pair type analysis. The goal is a recommendation - what R group should I put on next?

Now, any such approach is going to have to deal with this paper from Abbott in 2008. In that one, an analysis of 84,000 compounds across 30 targets strongly suggested that most R-group replacements had, on average, very little effect on potency. That's not to say that they don't or can't affect binding, far from it - just that over a large series, those effects are pretty much a normal distribution centered on zero. There are also analyses that claim the same thing for adding methyl groups - to be sure, there are many dramatic "magic methyl" enhancement examples, but are they balanced out, on the whole, by a similar number of dramatic drop-offs, along with a larger cohort of examples where not much happened at all?

To their credit, the authors of this new paper reference these others right up front. The answer to these earlier papers, most likely, is that when you average across all sorts of binding sites, you're going to see all sorts of effects. For this to work, you've got a far better chance of getting something useful if you're working inside the same target or assay. Here we get to the nuts and bolts:

The predictive method proposed, Matsy, relies on the hypothesis that a particular matched series tends to have a preferred activity order, for example, that not all six possible orders of [Br, Cl,...

Source: In the Pipeline - March 17, 2014 Category: Chemists Tags: In Silico Source Type: blogs