Affinity, ligand efficiency

In a catabolic or deconstructive, process, a higher-affinity inhibitor is decomposed into fragments by retrosynthetic means. The catabolic approach is no different from typical LLDD and does not need to be evaluated here (although, as noted below, a different paradigm, ligand efficiency, is needed to drive the process forward). This is no different to what is routinely done to optimize lead-like molecules. Often it is assumed that... 

A good way to compare ligands with different affinities/potencies and molecular weights is to normalize the affinity/potency with the ligand size.19,101 This is called ligand efficiency (LE), with the following definition 1101... 

Figure 11.5 Binding affinity analysis using SPR. Based on the original NMR hit (1), we identified structurally related compounds with improved binding, nd, not determined LE, ligand efficiency, explained in the text.

Figure 11.7 Affinity versus heavy atom count for selected compounds. Lines illustrate profiles at fixed ligand efficiency (0.35, 0.30, 0.25) over the range of affinity and heavy atom count. Point A designates an idealized compound with 36 heavy atoms (approximate MW 500 Da ) and affinity 10 nM). Numbers correspond to compounds described in the text.

As described above, it was known that N3 methylation was favored for the isocytosine series. The analogous compound in the dihydroisocytosine series (17) was then prepared and this resulted in a further improvement in affinity (IC50 79 p,M) and maintenance of high ligand efficiency. 

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