Practical Fragments has had quite a few
posts on ligand efficiency (see here, here, and here, for starters). Ligand
efficiency (LE) is defined simply as the free energy of binding for a ligand
divided by the number of heavy atoms in the ligand. One of the criticisms of LE
is that the definition of free energy depends on the definition of standard
state, which may be different on different planets. With the discovery of
silicon-based life on Venus, this is no longer just an academic argument.
Indeed, a recent paper in Venusian
Analytical, Physical, & Inorganic Discoveries describes an excellent
case study.
Professor Perelandra and
colleagues at East Eistla University performed a crystallograhic fragment
screen on the enzyme silica hydratase, which is essential for the life cycle of
the viciously parasitic Crystalline Horde. Fragment 1 binds in the active site,
and although it has low affinity, structure-guided medicinal chemistry rapidly
led to compound 42, with low nM activity in vitro and good efficacy in a silicon
resorption model.
Things get even more interesting
when you calculate the ligand efficiency values. The Venusians define standard
temperature and pressure very differently from us. More importantly, they don't
believe that standard state concentration should be 1 M. Given the extreme
conditions on their home world, they choose a standard state concentration of
10 M.
LE = - ΔG/HA
(where HA = number of
non-hydrogen atoms)
Thus, LEVenus =
-RTln(KD/[A]0)/HA
(where T = 737 K and [A]0
= 10 M)
Using our terracentric
definitions, the (impressive) LE of the fragment hit stays roughly the same
during optimization, suggesting that the medicinal chemists have done a good
job. However, by Venusian standards, the LE decreases!
This rock-solid example shows
that Dr. Saysno was right: ligand efficiency is arbitrary and should never be
used – on Venus.
Posts
3 comments:
Good one!
The authors did not mention, that skiing in April is wonderful on Venus. Otherwise, great research ;)
Jesting aside, as near as I can tell this post accurately summarizes Pete's criticism of ligand efficiency. What I found interesting when writing it was how insensitive LE is to the definition of standard state: it actually took quite a bit of tweaking to contrive an example where Terran ligand efficiency increased while Venusian ligand efficiency decreased. In other words, the criticism is irrelevant, at least for Earthlings.
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