Ligand efficiency: nice concept, shame about the metrics (poster for EuroQSAR 2016 in Verona)

1. LIGAND EFFICIENCY: NICE CONCEPT, SHAME ABOUT THE METRICS
Peter W Kenny
Grupo de Estudos em Química Medicinal – NEQUIMED, Instituto de Química de São Carlos,
Universidade de São Paulo, Av. Trabalhador Sancarlense, 400, 13566-590 São Carlos, SP, Brasil
pwk.pub.2008@gmail.com | http://fbdd-lit.blogspot.com (Molecular Design blog)
Ligand efficiency metrics are used to ‘normalize’ potency with respect to risk factor. What do they mean by
‘normalize’? Wouldn’t it be better to use the trend actually observed in data for normalization?
Using lipophilic efficiency to normalize potency with respect to lipophilicity is equivalent to assuming a unit
response (DpIC50/DlogP) to this risk factor. LipE (LLE) can be interpreted as a measure of the ease of
transferring a compound from octanol to its binding site provided that the compound binds in neutral form.
A concentration unit of mol/litre (M) is built into most definitions of ligand efficiency. This is equivalent to
assuming that affinity (pKd) or potency (pIC50) tends to 1 M in the limit of zero molecular size. The free
energy for formation of a ligand-protein complex depends on the (arbitrary) concentration that defines the
standard state: DG = DH TDS = RTln(Kd/C0)
Plotting affinity against risk factor allows us to test validity of assumptions on which ligand efficiency metrics
are based and the residual quantifies extent to which affinity of a compound beats the trend in the data
Scaling transformation of parallel lines by dividing Y by X
(This is how ligand efficiency is calculated)
Offsetting transformation for lines by subtracting X from Y
(This is how lipophilic efficiency is calculated)
Reference: Kenny, Leitão & Montanari (2014) JCAMD 28:699-701 DOI
Green: Y = aX + b
Purple: Y = aX
Blue: Y = X + b
PKB data from Verdonk & Rees (2008)
ChemMedChem 3:1179-1180 DOI