Ligand efficiency in action

At an introductory talk I was giving recently on FBLD, someone asked how useful ligand efficiency (LE) really is. A paper published online in J. Med. Chem. by Daisuke Tanaka and colleagues at Dainippon Sumitomo Pharma illustrates how the metric can guide medicinal chemistry to superior molecules.

The enzyme soluble epoxide hydrolase (sEH) is a potential anti-inflammatory target. Inhibitors have been reported, but these tend to be quite lipophilic, so the researchers sought to find smaller, less hydrophobic inhibitors that bound with high-affinity to the target. A virtual screen against multiple ligand-bound crystal structures led to the selection of 735 diverse compounds which were tested in a biochemical assay, resulting in 68 compounds with IC50 values better than 1 micromolar. Most of these were relatively hydrophobic amides or ureas.

After removing known chemotypes and obviously unattractive molecules, the researchers were left with 42 compounds. They decided to eliminate compounds with MW > 380 or logP > 3.5, leaving 17 compounds; as might be expected, these smaller molecules turned out to be the most ligand-efficient of the bunch. Despite being one of the weakest hits identified, fragment-like compound 1 was the most ligand efficient and was chosen for lead optimization. A crystal structure of this compound bound to sHE guided parallel synthesis of 155 analogs, all with low molecular weights. Many of these compounds were very potent, and compound 11 not only showed a nice improvement in affinity but also demonstrated good ADME properties.

The authors conducted a retrospective analysis using some of the other ligand-efficiency-like indices such as %LE and fit-quality, which allow looser standards for affinity as molecule size increases. Interestingly, compound 1 was not an obvious starting point using these metrics. It is impossible to say what would have happened had these measures been prioritized over ligand efficiency, but the success of the simpler LE suggests that taking size into account would not have been useful, and could even have been misleading.

This paper is not a traditional fragment paper in which a low affinity lead is optimized; the initial hit was already quite potent. Rather, as the authors note, this is a nice example of “fragment-inspired medicinal chemistry, in which the essence and advantages of FBDD are faithfully respected.” It also provides another example of how focusing on ligand efficiency, rather than just potency, can lead to attractive chemotypes.