Ligand efficiency invalidated!

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, LE_Venus = -RTln(K_D/[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.