Our last post discussed the growing plague of molecular obesity, and how numerous metrics have been designed to control it. In a paper published online in J. Comput. Aided Mol. Des. Paul Mortenson and Chris Murray of Astex describe a new one: LLEAT.
Although ligand efficiency (LE) is probably the most widely used and intuitive metric, it does not take into account lipophilicity. Other indices do, notably ligand lipophilicity efficiency (LLE) and ligand-efficiency-dependent lipophilicity (LELP), but these both have drawbacks for evaluating fragments. LLE (defined as pIC50 – log P) is not normalized for size; for a fragment to have an (attractive) LLE ≥ 5 it would need an exceptionally low log P or an exceptionally high affinity. LELP, defined as log P / ligand efficiency, is also potentially misleading since a compound could have an acceptable LELP value even with a low ligand efficiency if the log P is also very low.
To address these problems, Mortenson and Murray have tried to strip out the non-specific binding a lipophilic molecule experiences when going from water to a binding site in a protein. They define this modified free energy of binding as:
ΔG* = ΔG - ΔGlipo
≈ RT ln (IC50) + RT ln (P)
≈ ln (10) * RT (log P - pIC50)
In order to put values coming out of this metric on the same scale as those from ligand efficiency, they add a constant, such that:
LLEAT = 0.11 – ΔG* / (number of heavy atoms)
Thus, just as in ligand efficiency, the goal is for molecules to have LLEAT ≥ 0.3 kcal/mol per heavy atom.
The index has some interesting implications. For example, the two fragments below have the same number of heavy atoms, and thus if they had the same activity they would have the same ligand efficiency; on this measure alone, neither would be preferred as a starting point for further work. However, because of their very different lipophilicities, fragment 2 would need to be 45 times more potent than fragment 1 in order to have the same LLEAT of at least 0.3.
AT at 0.3, the phenyl would need to produce a 460-fold boost in potency while the piperazinyl would need to improve potency only 3-fold. This is consistent with what other folks have reported qualitatively, but it’s nice to have a simple quantitative measure.
Although some people may groan at yet another index, and no metric is perfect, I like the fact that this one is intuitive and has the same range of “acceptable” values as ligand efficiency. What do you think – is it useful?