12 March 2012


Besides ligand efficiency (LE), a slew of other metrics has been proposed to help evaluate what compounds to take forward in drug discovery. As seen in our poll and a recent round-table discussion, lipophilic ligand efficiency (LLE) is quite popular:
LLE = pIC50 (or pKi) – ClogP (or logD)
However, because this metric is not size-adjusted, it is not particularly useful for evaluating fragments, which often have low potency. In contrast, the metric LELP accounts for size:
LELP = logP / LE (where LE = ligand efficiency)
In a recent issue of J. Med. Chem., György Keserű and colleagues evaluate how these two metrics compare in a variety of settings.

The authors examine eight different compound sets: fragment hits and derived leads, HTS hits and derived leads, leads that subsequently became drugs (ie, “successful leads”), development candidates, compounds that entered phase II trials, and drugs on the market. Not surprisingly, drugs and phase II compounds had better LLE and LELP scores than other molecules. Also not surprisingly, fragments scored misleadingly poorly on the basis of LLE but well on the basis of LELP. What is perhaps unexpected, though, is that LELP was better at identifying successful leads than was LLE. Moreover, when compounds were evaluated for pharmacokinetic and safety parameters, LELP was more effective at predicting problems than was LLE. The authors state:
In summary, evaluation of pharmacokinetic and safety parameters revealed that LELP has benefits over LLE, as compounds with acceptable in vitro ADMET profiles are discriminated from compounds with significant liabilities.
Despite these potential advantages, LELP doesn’t seem to be widely used, perhaps because it is less intuitive than some of the other metrics. Indeed, it would be interesting to see these studies repeated using LLEAT, which also takes lipophilicity into account but has the same scale as LE.

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