Group Contribution revisited (via Fragment Based Drug Design)

"What chemists really need is reliable data, and biophysical techniques" [FBDD events 2009]

(via practical fragments)

In the world of fragment-based ligand discovery, researchers hope that two fragments, when linked together, will behave at least additively: the free energies of binding for each fragment will sum together, with a multiplicative effect on affinity. In ideal cases, linked fragments will behave synergistically. But all too often, linking two fragments produces disruptive behavior, and the resulting molecule actually binds less tightly than would be predicted based on the binding energies of the individual fragments. This occurs not just when linking fragments, but in fragment merging and growing as well. Can such phenomena be modeled?
The mathematical groundwork was described more than forty years ago by Spencer Free and James Wilson at the old Smith Kline and French company, and came to be known as a Free-Wilson analysis. In a nice update of this work, Julen Oyarzabal and co-workers have applied this technique to ... a variety of different targets, including a kinase, GPCRs, ion channels, and P450s.
...
But even if synergy is elusive, the paper suggests that you’ve got a better than even shot of producing a whole that is at least equal to the sum of its parts.

For an excellent pragmatic review about FBDD see also the comments in FBDD events 2009.