Lipophilic ligand efficiency

This chapter will summarize recent developments regarding the role of physicochemical properties in safety liability and the emerging use of physicochemical property-based lead optimization using lipophilic ligand efficiency (LLE or LipE). 

Lipophilic ligand efficiency (LLE) is a more recent concept than LE and has been implicated in toxicity resulting from promiscuous receptor interactions, which are driven mainly by lipophilicity. It was proposed" that LLE values of... 

Although this measure of ligand efficiency is the most widely used, it has been proposed that the LE index could be replaced by size-independent indices like the fit quality score (FQ) [19] or the percentage LE [20], which allow the comparison of fragments irrespective of their molecular weight. Many other related indices (listed in Table 1) have also been proposed recently to take into account properties other than molecular weight in the fragment-to-lead optimization, such as polar surface area or lipophilicity [20]. 

Select appropriate metrics for multidimensional optimization use ligand efficiency and lipophilic efficiency metrics in hit-to-lead optimization and change to more complex metrics emphasizing dosage to support lead optimization. 

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