Last year we highlighted a provocative article from Michael Shultz in which he took aim at the concept of ligand efficiency (LE). As we noted at the time, he raised some good points, and I am the first to argue that there is value in questioning widespread assumptions.
However, in addition to questioning the utility of LE, Shultz also questioned its mathematical validity. He repeated the attack earlier this year by asserting that ligand efficiency was a “mathematical impossibility.”
This is incorrect.
To set the record straight, Chris Murray (Astex), Andrew Hopkins (University of Dundee), György Keserü (Hungarian Academy of Sciences), Paul Leeson (GlaxoSmithKline), David Rees (Astex), Charles Reynolds (Gfree Bio), Nicola Richmond (GlaxoSmithKline) and I have written a response just published online in ACS Med. Chem. Lett. demonstrating that ligand efficiency is mathematically valid.
One of the criticisms of LE is that it is more sensitive to changes in small molecules (such as fragments) than in larger molecules. However, this is a property of any ratio, and we show that the same behavior applies to more familiar examples such as fuel efficiency: a few blocks of stop-and-go traffic has more of an effect on the overall fuel efficiency of a short trip than a long trip.
Of course, that’s not to say that ligand efficiency and other metrics are perfect or universally applicable; we discuss a number of situations where they may be more or less useful.
In this spirit, Practical Fragments is revisiting a poll from 2011 to see what metrics you use – please vote on the right-hand side of the page, and share your thoughts here. Note that you can vote for multiple metrics, and please check the last box (Polldaddy does not tally individual responses, so this box will track total number of voters to allow us to calculate percentage of respondents who use a given metric).
Keep the comments coming, and check back to see the poll results.