Ligand efficiency

As an example, Fig. 17.4 presents the ligand efficiency of 107 compounds active against human 5-hydroxytryptamine lA receptor (data extracted from GVKBIO). Compounds A and B have different potencies (IC5oA= 12.2pM and IC5oB= 1.0 pM) and properties (MWA=244, HAA=18, CLOGPA=2.8 and MWB=294, HAB=22, CLOGPB = 4.1), but display a similar LE of 0.37. 

The idea of ligand efficiency was extended by considering other molecular descriptors. Abad-Zapatero and Metz [56] introduced a percentage efficiency index, a binding efficiency index and a surface-binding efficiency index by normalizing 

IC5o=1.0pM, MW=294, HA=22). Open circles indicate compounds with R05 1 (at least one parameter from Lipinski s Rule-of 5 is out of range). Activity data extracted from GVKBIO. 

Combining molecular properties with potency provides a simple yet powerful overview of a screening dataset and can be used to quickly identify ligand-efficient lead-like compounds. In Fig. 17.5, a set of 429 compounds active against 5-hydroxytryptamine lA receptor are displayed in a PSA-ClogP plot with the size of the circle related to ligand efficiency. One can easily spot the efficient binders in area of favorable properties. 

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Hopkins, A. L., Groom, C. R., and Alex, A. (2004). Ligand efficiency A useful metric for lead selection. Drug Disc. Today 9 430-431. 

Fig. 17.5 Plot of ClogP versus PSA for a set of ligand efficiency. Such visualization is useful 429 compounds active against 5- to identify ligand-efficient lead-like...

Abad-Zapatero, C., Metz, J. T. Ligand efficiency indices as guideposts for drug discovery. Drug Discov. Today 2005, 10, 464 69. 

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). 

This shows that the strong chelating effect of the bidentate ligand efficiently retains the metal attached to the support. 

Caspase 1 (Table 1, entry 4) Another protease screened using fragments is caspase 1. Using a tethering approach (described earlier) active sub-site binders were identified and then linked to produce a sub-micromolar inhibitor 24. Further optimisation by rigidifying the linker produced a ligand-efficient nanomolar inhibitor 25 [38]. 

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