Ligand efficiency hot spots

Hot spots are regions of a protein with a particular predilection for binding to small molecules – thermodynamic sinkholes, so to speak. Discovering one of these can get you to potent molecules very quickly. In an effort to better understand hot spots, Iwan de Esch and colleagues at VU University in Amsterdam and collaborators at Beactica have deconstructed a potent ligand for nicotinic acetylcholine binding protein (AChBP), a model protein for ligand-gated ion channels, which are implicated in a variety of neurological diseases. They report their results in a recent issue of J. Med. Chem.

The researchers started with the previously reported quinuclidine compound 6 (see figure) and fragmented this into 20 analogs. They tested these in a surface plasmon resonance (SPR) assay as well as in a more conventional radioligand binding assay; the agreement between these very different assay formats was excellent, further validating the utility of SPR as a useful tool for discovering fragments.

Not surprisingly, some of the fragments have higher ligand efficiencies than the larger, more potent molecule, suggesting that there is a hot-spot that recognizes the core fragment 25 (which is structurally related to nicotine). This concept of “group efficiency” has been described previously, and can be useful for optimizing fragments. For example, compound 22, without a basic nitrogen atom, has the lowest ligand efficiency in the bunch; presumably, simply adding the nitrogen would give a sizable boost in potency.

However, one needs to be cautious. The researchers use computer docking to develop models of how each of these fragments bind, but as we have seen before, isolated fragments do not always recapitulate the binding modes of fully elaborated molecules. Still, particularly in the absence of structure (as is the case with many ion channels), exercises such as this could provide useful ideas for what to do with fragment hits.